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array:23 [ "pii" => "S2445146023000651" "issn" => "24451460" "doi" => "10.1016/j.vacune.2023.10.009" "estado" => "S300" "fechaPublicacion" => "2023-10-01" "aid" => "302" "copyright" => "Elsevier España, S.L.U.. All rights reserved" "copyrightAnyo" => "2023" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Vacunas. 2023;24:348-57" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:17 [ "pii" => "S2445146023000663" "issn" => "24451460" "doi" => "10.1016/j.vacune.2023.10.010" "estado" => "S300" "fechaPublicacion" => "2023-10-01" "aid" => "283" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Vacunas. 2023;24:358-63" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "CHECKvacc (HOV3, CF33-hNIS-anti-PD-L1), the next medical revolution against cancer" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "358" "paginaFinal" => "363" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "CHECKvacc (HOV3, CF33-hNIS-anti-PD-L1), la siguiente revolución médica contra el cáncer" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "f0005" "etiqueta" => "Fig 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1216 "Ancho" => 2008 "Tamanyo" => 231913 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Schematic showing mechanism of action of CF33-hNIS-antiPDL1.<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">14</span></a></p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ali Adel Dawood" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Ali Adel" "apellidos" => "Dawood" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146023000663?idApp=UINPBA00004N" "url" => "/24451460/0000002400000004/v2_202401230726/S2445146023000663/v2_202401230726/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S244514602300064X" "issn" => "24451460" "doi" => "10.1016/j.vacune.2023.10.008" "estado" => "S300" "fechaPublicacion" => "2023-10-01" "aid" => "297" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Vacunas. 2023;24:341-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special Article</span>" "titulo" => "COVID-19 immune response in adults post Measles-Rubella vaccination" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "341" "paginaFinal" => "347" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Respuesta inmunitaria a la COVID-19 en adultos después de la vacunación contra el sarampión y la rubéola" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "f0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1115 "Ancho" => 1423 "Tamanyo" => 55997 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Increased anti-SARS-CoV-2 IgM levels before and after being given the MR vaccine.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Suwoyo Suwoyo, Erna Rahma Yani, Koekoeh Hardjito" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Suwoyo" "apellidos" => "Suwoyo" ] 1 => array:2 [ "nombre" => "Erna Rahma" "apellidos" => "Yani" ] 2 => array:2 [ "nombre" => "Koekoeh" "apellidos" => "Hardjito" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S244514602300064X?idApp=UINPBA00004N" "url" => "/24451460/0000002400000004/v2_202401230726/S244514602300064X/v2_202401230726/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review Article</span>" "titulo" => "ERX-41; Promising compound by targeting LIPA is a new Achilles heel therapeutic strategy for hard-to-treat solid tumors by induction of endoplasmic reticulum stress" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "348" "paginaFinal" => "357" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Majid Eslami, Mohammad Memarian, Bahman Yousefi" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Majid" "apellidos" => "Eslami" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "af0005" ] ] ] 1 => array:3 [ "nombre" => "Mohammad" "apellidos" => "Memarian" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "af0010" ] ] ] 2 => array:4 [ "nombre" => "Bahman" "apellidos" => "Yousefi" "email" => array:1 [ 0 => "yosefi_bahman@semums.ac.ir" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "af0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "af0020" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cr0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran" "etiqueta" => "a" "identificador" => "af0005" ] 1 => array:3 [ "entidad" => "Department of Internal Medicine, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran" "etiqueta" => "b" "identificador" => "af0010" ] 2 => array:3 [ "entidad" => "Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran" "etiqueta" => "c" "identificador" => "af0015" ] 3 => array:3 [ "entidad" => "Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran" "etiqueta" => "d" "identificador" => "af0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cr0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "ERX-41; El compuesto prometedor de targeting LIPA es una nueva estrategia terapéutica del talón de Aquiles para tumores sólidos difíciles de tratar mediante la inducción del estrés del retículo endoplásmico" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "f0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1929 "Ancho" => 2756 "Tamanyo" => 537865 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">ERX-41 binds LAL and is independent of lipase activity. ERX-41 binds to the LXXLL domain of LAL protein and induces ER stress, resulting in apoptosis and cell death. LAL localization to the ER is critical for ERX-41 activity. ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. Three ERS sensors IRE1α, PERK, and ATF6 cooperatively organize UPR signaling. ERX-41 is a potent therapeutic agent for hard treat tumor through disruption of protein folding and induction of ER stress.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">The endoplasmic reticulum (ER), one of the key sub-cellular and mobile organelles, is known to regulate a variety of significant cellular processes, including as protein production, folding, misfolding, and unfolding; synthesis and transport of lipids; and the upkeep of cellular calcium homeostasis. The ER generates a substantial membrane-like structure in its cytoplasm, and this organelle's membrane has a number of tasks, including controlling intracellular signaling pathways, maintaining calcium homeostasis, and folding newly generated proteins. A nuclear envelope domain, which is incorporated into rough ER, and an ER domain for ribosome synthesis make up the ER structure.<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a> Before these proteins are transported outside of the ER, a number of chaperones that are linked with the ER help to ensure appropriate folding and modification. Only correctly folded proteins can be delivered to the Golgi apparatus, and ER chaperones help fold nascent proteins in the ER. Proteins that are unfolded or misfolded must be retrotranslocated to the cytoplasm by the ER-associated degradation (ERAD) machinery and then destroyed by the proteasome in order to prevent ER stress, which can further lead to cell death and ER-associated disorders. The success rate for optimal protein folding is poor despite the robustness of this machinery because of the vast spectrum of cellular disturbances that interfere with its effectiveness. Dysregulation of these pathways in the ER is consequently linked to the emergence and spread of cancer.<a class="elsevierStyleCrossRef" href="#bb0010"><span class="elsevierStyleSup">2</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">There are numerous areas of high scientific interest that will be significantly impacted by the precise delivery of different medicines, probes, or peptides to the ER. Diverse cellular responses and cell fates will result from the same medications and therapies when they are localized in different subcellular locations. Through the triggering of apoptosis, clinical oncology has been working for decades to eradicate cancer cells. Therefore, one frequent method of treating cancer is by inducing ER stress.<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a> Compared to normal cells, cancer cells have higher baseline ER stress response system activity. As a result of its role in carcinogenesis and development, ER stress signaling has emerged as the new weakness in the development of cancer therapies. Targeting the ER in cancer cells has emerged as an intriguing unconventional approach in next-generation anticancer therapy. Small chemical discovery to specifically target the ER for cancer therapy, however, remained challenging and unexplored.<a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">ER STRESS induction and unfolded protein response</span><p id="p0015" class="elsevierStylePara elsevierViewall">In a healthy state, ER controls transcription factors, participates in protein folding and degradation, and promotes homeostasis. Cells experience a state called ER stress, which is considered by misfolded proteins accumulating inside the ER luz, when the ER's capacity for folding proteins is exceeded. Numerous factors, including food deprivation, hypoxia, and calcium depletion, can affect the compartment's homeostasis and cause an ER stress state. Cells have developed an evolutionary conserved signal transduction system whose main goal is to restore ER homeostasis so as to overcome the unbalanced ER protein-folding capacity.<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> The unfolded protein response (UPR), a cytoprotective program, is started by many mechanistically branching mechanisms that control the expression of numerous genes that resolve this ER stress and preserve homeostasis or trigger apoptotic signals in the event that the stress is not mitigated. Thought to be mechanisms for cell self-defense, autophagy and UPR signaling pathways will instead activate the mechanism of cell death as cellular stress severity or duration increases. As a result, UPR serves as the foundation for some anti-cancer patterns' pro-apoptotic pathways. During times of cellular stress, ubiquitin ligase regulates the amount and duration of mitochondrial activity.<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">The inflammatory response, on the other hand, is the human immune system's initial response to a foreign body infection or tissue damage and can help to protect the body from harm. However, persistent inflammation that lasts for a long time and is incurable is bad for the health. The development of different malignant tumors, including hepatocellular carcinoma, lung cancer, and breast cancer, has also been demonstrated in numerous studies to be significantly influenced by inflammatory responses.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a> The developing polypeptide folds and unfolds in the ER luz as the protein spirals out of control in an increasing amount of intracellular production. Misfolded protein accumulation disturbs ER homeostasis and initiates UPR. In addition to being necessary for cell homeostasis and embryogenesis, stress and UPR are involved in the etiology of inflammatory illnesses because they can cause inflammatory responses in specific cells and tissues.<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">Because malignant tumor cells must recycle their organelles to maintain development, ER stress can successfully trigger autophagy in cells with various malignancies. In addition to reducing ER stress-induced ER enlargement, autophagy also improves cell survival and non-apoptotic death. Through protein overload, oxidative stress also has an impact on how vital proteins function in the mitochondria.<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a> Basic organelle function is lost when harmful chemicals build up in the ER and mitochondria. It is well known that prolonged ER stress can also activate the UPR pathway to cause an inflammatory response. The formation of tumors is assumed to be linked to inflammatory response. Depending on the state of the cell, the UPR can be both cytotoxic and cytoprotective. The UPR's goal is to balance the environment for ER folding under ER stress. Tumor cells will die if ER stress persists and the UPR is unable to return ER equilibrium. Along with induced tumor dormancy, the UPR can also shield tumor cells from apoptosis, allowing the tumor to develop again when favorable conditions have been restored. Numerous physiological and pathological triggers, as was already indicated, can result in ERS, which then sets off UPR. Cells will alter transcriptional and translational patterns through homeostatic UPR (hUPR) in response to a mild to moderate (yet persistent) ERS, which encourages cell adaptability and improves cell survival. The cell's UPR will be dominated by terminal UPR as the ERS advances to the point that hUPR is insufficient to restore equilibrium (tUPR). To stop ongoing cell harm, this mechanism will actively start cell apoptosis.<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a></p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Signaling pathways related to ERS and UPR</span><p id="p0030" class="elsevierStylePara elsevierViewall">By modifying the cascade of ER-associated degradation (ERAD) systems that encode chaperone proteins and the cascade of transcription factor-mediated gene expression of the component genes, UPR primarily aims to reduce protein production and recovery. Mechanical autophagy and cell survival are maintained via cell homeostasis. Additionally, through altering UPR signals, UPR activation might impair these activities by causing alterations in intracellular mitochondrial function or autophagy.<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a> Inositol-requiring enzyme 1 (IRE1), pancreatic endoplasmic reticulum kinase (PERK), and activating transcription factor 6 are the three ER-transmembrane stress sensors that regulate the UPR (ATF6). The major and most prevalent ER-resident chaperone BIP/GRP78 binds to the luminal domains of these sensors to prevent their activation under physiological circumstances (78-kDa glucose-regulated protein). In actuality, BIP creates a dynamic equilibrium between the intra-luminal domains of the three ER stress sensors and unfolded proteins that need to be folded. A compromised balance caused by accumulated unfolded proteins causes BIP to separate from ER stress sensors and engage in enormous protein folding cooperation (due to its higher natural affinity to unfolded proteins compared to ER stress sensor luminal domains). ATF6's translocation to the Golgi apparatus and subsequent activation, together with the homodimerization of IRE1 and PERK and their trans-auto-phosphorylation and activation, are the results of this disequilibrium.<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a> By separating Grp78/binding immunoglobulin protein (Bip), a key chaperone protein, from three membrane-bound ER stress sensors, including PERK, ATF6, and IRE1, cells attempt to maintain normal folding processes in the ER through the UPR process. After recognizing proteins separate from Grp78/Bip, these sensors are activated in a particular order, starting with PERK, which prevents general protein synthesis by phosphorylating eIF2. During times of cellular stress, these mechanisms also result in the suppression of the transcription factor NF-κB (<a class="elsevierStyleCrossRef" href="#f0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0035" class="elsevierStylePara elsevierViewall">Another transcription factor that regulates gene expression is ATF6, which is activated by translocation to the Golgi apparatus. There, ATF6 is cleaved and the active form of the transcription factor is released. The transcription of genes encoding chaperones or folding enzymes involved in protein folding, secretion, or ER-associated protein degradation (ERAD) is activated after IRE-1 is activated and its downstep is followed by the splicing of XBP1. A chaperone protein termed glucose-regulated protein 78 (GRP78) in the ER binds to the intraluminal domains of the three transmembrane proteins and inhibits their activity when the ER is in a homeostatic state. The three transmembrane proteins will separate from GRP78 and activate three parallel UPR signaling pathways when there is an excessive buildup of misfolded and unfolded proteins in the ER. This will lessen the burden brought on by these proteins in the ER. They function by either reducing translation to lessen the need for newly produced proteins to fold or by directing unfolded proteins into the cytoplasm for ubiquitination and degradation via the ERAD pathway (<a class="elsevierStyleCrossRef" href="#f0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a></p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">ER stress-mediated apoptosis in chronic or excessive conditions</span><p id="p0040" class="elsevierStylePara elsevierViewall">The primary form of programmed cell death (PCD), apoptosis, is a crucial target for the development of anticancer drugs. Cancer cells' extrinsic and intrinsic mechanisms are primarily responsible for triggering apoptosis. Members of the death receptor family start the extrinsic route. The death-inducing signaling complex (DISC) is created as a result of the interaction between death receptors and their ligands, and it finally activates caspase-8. The intrinsic pathway, also known as the mitochondrial pathway, is triggered by DNA damage, growth factor depletion, osmotic pressure changes, and cytotoxic stimulation of anticancer agents. The intrinsic pathway then controls the expression of pro- and anti-apoptotic proteins, thereby activating caspase-9 and caspase-3.<a class="elsevierStyleCrossRef" href="#bb0065"><span class="elsevierStyleSup">13</span></a> The buildup of unfolded proteins in the ER can be detected by the UPR. When the ER's function doesn't return to normal, the protein response increases the ER's capacity to fold proteins and triggers death. Chronic ER stress damages cells internally or externally, activates the UPR, and impairs intracellular calcium and redox balance. When UPR fails to keep the ER in balance due to persistent or extreme ER stress, the apoptotic signaling pathways become active and even cause cell death. Through the three main signaling pathways of the CHOP pathway, JNK pathway, and caspase-12 pathway, ER stress can cause apoptosis.<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">14</span></a> When the homeostasis is upset, a number of factors prevent proteins from folding correctly, including a lack of cellular energy or molecular chaperones, a shortage of Ca2<span class="elsevierStyleHsp" style=""></span>+, oxidative environmental damage, protein variation, and disulfide bond breakdown. For these cells to survive, ER stress and dysfunction must be overcome. An increase in transcription of Bcl2-like11 (BIM), p53 unregulated modulator of apoptosis (PUMA), NADPH oxidase activator (NOXA), and BH3-only proteins is brought on by the imbalance between anti- and pro-apoptotic Bcl-2 proteins caused by ER stress. ER stress encourages the connections between PUMA and Bax, which releases cytochrome c and causes apoptosis through the caspase-dependent cleavage of p53.<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a></p><p id="p0045" class="elsevierStylePara elsevierViewall">In tumor cells, ER stress may lead to the restoration of homeostasis and the creation of an environment that is favorable for the survival and growth of the tumor. Numerous stressful circumstances, like hypoxia, food deprivation, pH changes, or poor vascularization, might limit the development of tumor cells and thus activate the UPR. ER stress is brought on by nutritional overabundance in healthy cells as well as food deficiency in malignant cells. The high rates of cancer cell proliferation during carcinogenesis necessitate higher ER protein folding, assembly, and transport, which can result in physiological ER stress. The ER stress response is thought to be cytoprotective and is implicated in tumor development and environmental adaption.<a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a> ER stress showed pro-survival effects on tumor formation and progression in a mouse model of a human tumor. ATF4, which is upregulated in tissues from human breast cancer patients with severe hypoxia, and spliced XBP1, which is raised in breast cancer, lymphoma, and glioblastoma cells, are other ER resident proteins that contribute to tumor survival. In mice with human tumor xenografts, PERK also fosters beta cell proliferation and encourages angiogenesis. However, in ways that are either UPR-dependent or independent, the ER stress response is also directly connected to proapoptotic pathways (<a class="elsevierStyleCrossRef" href="#f0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a></p><p id="p0050" class="elsevierStylePara elsevierViewall">Another potential anti-tumor tactic is to activate the CHOP-GADD34 axis. As CHOP is PERK's downstream target, there is strong evidence to suggest that PERK plays a significant role in ER stress-induced cell death. Loss of CCAAT/enhancer binding protein homologous protein (CHOP) has been shown to increase ER stress resistance in cells and live animals, indicating that CHOP triggers the cell death pro-gram. 36 In a similar manner, CHOP causes cell death in ER stress-exposed cells by encouraging protein production and oxidation (<a class="elsevierStyleCrossRef" href="#f0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a> In response to various ER stresses, such as the buildup of non-native proteins in the ER luz and lipid disequilibrium in the ER membrane, these three signaling pathways are triggered. The activation of these UPR pathways causes the ER and overall cellular physiology to undergo transcriptional and translational remodeling, which helps to reduce ER stress and encourage cellular adaptation in response to an acute shock. Through this action, the UPR serves as a defense signaling route that controls a number of cellular physiologic processes, such as the preservation of secretory proteostasis, proliferation, redox regulation, differentiation, and metabolism. However, sustained UPR activation results in pro-apoptotic signaling in response to persistent or serious ER insults that cannot be treated by protective remodeling. In order to control both protective and apoptotic signals in response to pathologic ER insults, the UPR thus plays a crucial function.<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a></p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">ER-targeting based on many approaches</span><p id="p0055" class="elsevierStylePara elsevierViewall">Agents that cause ER stress are also potential cancer treatments. This connection might be linked to the production of ER stress in tumor cells. To combat drug resistance, stress is a possible target for the creation of medications that interfere with particular signaling pathways to lessen inflammatory response, angiogenesis, and hypoxic adaption. Recent research has examined a number of anti-cancer drugs in relation to ER stress, which may either directly or indirectly effect malignancies. Targets unique to cancer cells have not yet been identified, yet. These medications' effects on non-tumorigenic cells are still being studied. Paradoxically, tumor cells can paradoxically be more resistant to anticancer treatments that induce ER stress than normal cells. Tumor cells have a high proliferative rate compared to nontumorigenic cells, which makes them demand efficient high-energy producing systems. As a result, tumor cells exhibit significantly higher levels of glycolysis than non-tumorigenic cells.<a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a> Hypoxia inducible factor 1 (HIF1) is a key player in the growth and development of tumors. It controls the production of glycolytic enzymes and mediates angiogenesis, proliferation, and invasiveness. In order to treat hypoxic malignancies, inhibiting the HIF1 signal may represent a new and potential therapeutic target.<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a></p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Small molecules</span><p id="p0060" class="elsevierStylePara elsevierViewall">The primary methods for treating cancer include medication, surgery, radiotherapy, and biotherapy. Chemotherapy is one approach that involves using chemical medications to either kill tumor cells or stop them from growing and proliferating. However, the major drawback of chemotherapy is that it cannot tell a difference between cancer cells and healthy cells, leading to high toxicity and adverse effects. Compared to conventional chemotherapy medications, there has been a remarkable shift in cancer treatment recently, moving away from broad-spectrum cytotoxic drugs and toward tailored treatments. Because of this, tailored medications can specifically target cancer cells while sparing healthy cells, allowing them to advance at a unique rate. Small molecules and macromolecules are the two types into which targeted medications can be divided. In comparison to macromolecule medications, small-molecule targeted pharmaceuticals have advantages in terms of pharmacokinetic (PK) features, pricing, patient compliance, drug storage and transportation, and patient compliance. These medications have a broad range of targets, including kinases, proteins that regulate epigenetic processes, enzymes that repair DNA damage, and proteasomes. Small-molecule focused anti-cancer medications undoubtedly yet face several difficulties, including low response rates and drug resistance.<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a> Small-molecule drugs are typically ≤<span class="elsevierStyleHsp" style=""></span>500 Da in size and are typically taken orally. Because of their tiny size, they may also cross the plasma membrane and interact with the cytoplasmic domains of cell-surface receptors and intracellular signaling molecules. In theory, tiny molecule drugs may be designed to target any part of a molecule, independent of its biological position.</p><p id="p0065" class="elsevierStylePara elsevierViewall">Small molecules containing ER-targeting moieties are one type of small molecule anti-cancer therapy (sulfonamide, chloride, glibenclamide, or amphoteric ionic ligand). Small compounds are amenable to both direct and indirect ER targeting because of their low molecular weight, changeable structure, and adaptable modification. Small molecules also highly accumulate in the ER through a specific interaction between the ER-targeting moiety and ER-corresponding receptor. Additionally, the ER membrane (EM) exhibits an amphiphilic character that can be used for ER-targeting by lipophilic membranes. Additionally, it is possible to encourage enzyme-mediated ER-specific targeting by taking advantage of the precise connection between ER-specific metabolic enzymes and their respective substrates. For instance, the ER-localized enzyme carboxylesterase (CE) hydrolyzes ester or amide prodrugs.<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a></p><p id="p0070" class="elsevierStylePara elsevierViewall">Several indirect ER-targeting techniques have also been used in numerous investigations, including the use of antibodies modified with particular signal peptides and the physiological makeup of the membrane that is connected with the ER and mitochondria. Small compounds that target different parts of the unfolded protein response have therefore been investigated, and ER physiology molecules like salubrinal, GSK2606414, and sunitinib are well known for manipulating one or more ER stress pathways. The development of ER-targeted medicines, however, is still in its infancy because to the dearth of targeting moieties, and as a result, there aren't many ER stress inducers and UPR inhibitors available. Therefore, there is a critical need to create new small compounds that can act as modulators of ER stress. Recent research has shown that a few chemicals build up inside the ER of cancer cells to cause ER stress. The presence of sulfonamide moieties in these small molecules is a noteworthy feature. Sulfonamide receptors are found on the surface of the ER, which makes it easier for small molecules to be internalized in the intracellular ER. Additionally, tiny compounds comprising sulphonamide and hydrazide-hydrazone showed a variety of biological activity, making them preferred structures for both natural and synthetic goods.<a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">24</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">From this angle, intriguing options include small molecule inhibitors of the kinase component of UPR like PERK and IRE1. The development of medicines that target the cytoprotective role of UPR while maintaining or boosting its promoting activity will be a challenge in the treatment of cancer. Additionally, recent research has shown that ER stress is strongly linked to and/or influences immunological responses as well as the immunogenicity of cell death processes brought on by specific anti-cancer treatments or modalities. Therefore, it appears crucial to combine the current paradigm of treatment (cell killing) with the inflammatory/immune potential of the ER stress/UPR pathway in the future. This will offer a fresh approach to the treatment of tumors.<a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a></p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">ERX-41: a novel small molecule target medication</span><p id="p0080" class="elsevierStylePara elsevierViewall">A new compound called ERX-41 has been created by scientists, and it may be able to treat a variety of malignancies that are difficult to treat, such as triple-negative breast cancer, by taking advantage of a flaw in cells that is not currently being exploited by existing medications. These findings are noteworthy because they offer a fresh strategy for combating the weakness of many aggressive tumors, which is their susceptibility to increased ER stress. This serious discovery concerned lysosomal acid lipase A (LIPA), a new therapeutic target, and its previously unknown function in protein folding. Indicate the potential and good therapeutic index to successfully treat patients with aggressive malignancies by targeting LIPA with ERX-41.<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a> In order to advance these medications into clinical trials and save the lives of patients with deadly diseases, ERX-41 altered protein folding in the cancer cell, producing ER stress and marketing itself as a first-in-class oral therapeutic that kills aggressive therapy-resistant tumors. Unlike fulvestrant and other selective ER-degraders like GDC-0810, tamoxifen, and ERX-11, ERX-41 does not interact with the ER-ligand-binding domain (LBD). They have different molecular targets: ERX-11 and ERX-41. An objective CRISPR-Cas9 knockout (KO) screen was carried out in MDA-MB-231 cells to determine the molecular target of ERX-41. Five of the top six genes—LIPA, SLC5A3, TMEM208, SOAT1, and ARID1A—were knocked out in TNBC cell lines, which were then tested for ERX-41 responsiveness.<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">In parental SUM-159 cells, ERX-41 activates PERK and induces p-eIF2-, but not in SUM-159 cells with LIPA KO, according to immunoblotting (<a class="elsevierStyleCrossRef" href="#f0010">Fig. 2</a>). The recognized ER stress inducers thapsigargin (inhibitor of ER Ca2<span class="elsevierStyleHsp" style=""></span>+ ATPase) or tunicamycin (blocks N-linked glycosylation) did not affect the inducibility of UPR genes in SUM-159 cells with LIPA KO. Patients with triple-negative breast cancer (TNBC), which lacks estrogen, progesterone, and human epidermal growth factor receptors, have fewer therapy options even though there are effective cures for ER-positive breast cancer patients. TNBC typically affects women under the age of 40 and has less favorable prognoses compared to other kinds of breast cancer. However, the remarkable discovery about the ERX-41 chemical was that it eliminated tumor cells regardless of whether the cancer cells contained estrogen receptors while sparing healthy cells. In actuality, it killed the ER-positive breast cancer cells less effectively than it did the triple-negative cells.<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a></p><elsevierMultimedia ident="f0010"></elsevierMultimedia></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">LIPA structure and functions</span><p id="p0090" class="elsevierStylePara elsevierViewall">The LIPA gene spans approximately 38 kb and has 10 exons. It is found on human chromosome 10q23.2–23.3. According to the RefSeq database, LIPA has 3 transcript variants. LAL from humans contains 399 amino acids (AAs). It is anticipated that the signal peptide (SP) sequence will consist of the first 27 AAs. 9 Although the function of the signal peptide sequence in LAL has not been experimentally verified, the signal peptide in many lysosomal proteins guides their cotranslational translocation to the ER for cleavage by the signal peptidase11. Following signal peptide cleavage, the proprotein of 372 AAs goes through cotranslational/post-translational glycosylation modification in the ER before being transported to the Golgi for the addition of M6P (mannose 6-phosphate),15 which is crucial for the hydrolase's lysosomal targeting. By hydrolyzing cholesteryl esters and triglycerides, lysosomal acid lipase (LAL), which is expressed by the lipase A (LIPA) gene, produces free fatty acids and cholesterol in the cell. In mice and humans with LAL deficiencies, the crucial part that LAL plays in lipid metabolism has been proven.<a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">27</span></a></p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">LAL protein's lysosomal subcellular location is related to its function as a LIPA</span><p id="p0095" class="elsevierStylePara elsevierViewall">In SUM-159 cells with overexpressed myc-tagged LAL, the capacity of ERX-41 to cause ER stress motivated an analysis of LAL subcellular location in TNBC utilizing coimmunofluorescence with both ER and lysosomal markers. Biochemical analysis of SUM-159 cell subcellular fractions demonstrated enrichment of LAL protein in the subcellular fraction that was abundant in ER. Also supporting its ER location is the glycosylated LIPA's sensitivity to endoglycosidase H (Endo H) and peptide-N-glycosidase F (PNGase F) breakage. Glycosylated LIPA would be susceptible to PNGase F but not to Endo H cleavage if glycosylation took place in the Golgi.<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a></p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Protein folding in the ER is disturbed by ERX-41's induction of ER stress</span><p id="p0100" class="elsevierStylePara elsevierViewall">It has been biochemically proven that ERX-41 induces ER stress and downstream UPR pathways by upregulating phosphorylated protein kinase R-like ER kinase (p-PERK) and phosphorylated eukaryotic translation initiation factor 2 subunit 1 (p-eIF2-), as well as by promoting the expression of CCAAT-enhancer-binding homologous protein (CHOP) and phosphorylated inos One dose of ERX-41 generates ER stress in vivo, as seen by increased p-PERK and p-eIF2- staining in TNBC xenografts within 24 h of therapy, as shown at the RNA level by ERX-41-induced spliced XBP1 in SUM-159, MDA-MB-231, and BT-549 cells but not in HMEC cells (<a class="elsevierStyleCrossRef" href="#f0010">Fig. 2</a>). These findings demonstrate that ERX-41 specifically produces ER stress because our PK experiments revealed that treated tumor tissues have measurable levels of the drug at 24 h. Global de novo protein synthesis in TNBC cells, but not in HMEC cells, is prevented by ERX-41 as a functional result of ERX-41 development of ER stress, as demonstrated by immunoblots for puromycin-labeled nascent proteins. These findings imply that ERX-41 can cause uncompensated ER stress, which shuts down ER activity and prevents protein synthesis, ultimately causing cell death. Using a recombinant LAL coupled to TurboID, the LAL interactome was well-defined in order to molecularly understand how targeting of LAL results in ER stress. Four of the top five biological processes are engaged in crucial ER protein maturation tasks, including protein folding in the ER, according to gene ontogeny (GO) study of the 54 LAL interacting proteins. Analysis of the cellular components revealed that the ER was where LAL binders were most frequently found. The expression of multiple ER-localized proteins involved in protein folding is impacted by ERX-41 binding to LAL in the ER, resulting in substantial ER stress/UPR and cell death.<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a></p><p id="p0105" class="elsevierStylePara elsevierViewall">The protein LAL protein, which is produced by the LIPA gene, is the target of ERX- 41, according to cellular thermal shift experiments. A simulation of in silico molecular docking showed how ERX-41 interacts with LAL. LAL only has one 239LXXLL243 motif, and ERX-41 might interact with this LXXLL motif. LAL's lipase activity appeared to be structurally unique from the LXXLL motif in terms of location. Lipase activity of LIPA was not inhibited by ERX-41, whereas Lalistat 2 (a selective inhibitor of LAL lipase activity) reduced lipase activity in SUM-159 cells. The lack of inhibitory activity on lipase function (from other lipases) in LIPA KO cells supports the specificity of Lalistat 2 for LAL. These results imply that the LXXLL motif is essential for the interaction between LAL and ERX-41 (<a class="elsevierStyleCrossRef" href="#f0010">Fig. 2</a>).<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a></p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075">Targeting LIPA in TNBC and solid tumors</span><p id="p0110" class="elsevierStylePara elsevierViewall">Tissue microarray analysis of LAL protein expression in TNBC revealed that ><span class="elsevierStyleHsp" style=""></span>80% of initial TNBC tumors exhibited considerable and detectable LAL protein expression, in contrast to decreased LAL expression in normal breast tissue. TNBC tumors were shown to express more proteins than the nearby normal breast tissue. It's significant that the glycosylation of LAL in TNBC tumors resembles that found in TNBC cells. Analysis of publicly accessible information from The Cancer Genome Atlas (TCGA) revealed that patients with BC who had high LAL expression had considerably lower overall survival rates. These findings imply that LAL is a potential molecular target for TNBC.<a class="elsevierStyleCrossRef" href="#bb0140"><span class="elsevierStyleSup">28</span></a> Immunohistochemistry-based testing of LAL expression in healthy mouse organs was inspired by ERX-41's low in vivo toxicity (IHC). LAL expression was much lower in mouse tissues than in tumor tissue in the uterus, liver, kidney, heart, lung, spleen, pancreas, and mammary fat pad. LAL expression was lowest in the spleen, liver, and kidney and highest in the liver, pancreas, and mammary fat pad. Given the function of the spleen in the lymphatic system, it is important to note that prior research found no impact of ERX-41 on plasma cells. These findings imply that increased LAL expression in tumors may be what causes that sensitivity to ERX-41.<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a></p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080">Discussion</span><p id="p0115" class="elsevierStylePara elsevierViewall">Despite the fact that the ER is a dynamic organelle that keeps cells in a state of homeostasis, the molecular mechanism of ER stress activation is complex and involves signaling pathways that activate the UPR in order to deal with ER stress and restore ER equilibrium. As a result, it was once believed that the UPR response brought on by ER stress constituted a self-regulating mechanism for defending cells against permanent harm. According to studies on many cancer types, whereas the surrounding healthy tissue does not, primary tumor cells can up-regulate the UPR signaling pathway.<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a> In this process, cellular DNA, RNA, proteins, lipids, and organelles that were damaged or unnecessary were broken down in order to recycle nucleosides, amino acids, and fatty acids that might later be employed as energy sources and cellular building blocks. To support cellular life, cells specifically employ a variety of adaptive protective mechanisms, such as translational attenuation, ER chaperone expression, and increased ERAD. A switch from a pro-survival to a pro-death response, such as apoptosis, which results in cancer cell death, is promoted by the creation of severe or unresolved ER stress in cancer cells. An effective phagocytic clearance, which prevents post-apoptotic necrosis and sets off an anti-inflammatory response, characterizes the cell death pattern known as apoptosis.<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a></p><p id="p0120" class="elsevierStylePara elsevierViewall">Deciphering the mechanism by which the ER stress pathway triggers cellular autophagy and inflammatory responses—or finding ways to prevent those represents a significant challenge for future research. To do this, it will be necessary to define the justification for drug design and a promising therapeutic strategy to boost the effectiveness of anticancer medications. However, persistent and severe ER stress kills cancer cells by inducing their autophagy, apoptosis, necroptosis or immunogenic cell death. Biochemical and ultra-structural studies, have shown that ERX-41 induces ER stress, shuts down de novo protein synthesis, blocks proliferation and induces apoptosis of TNBC in vitro, ex vivo and in vivo ERX-41 aggravates this already engaged system in TNBC to exhaust its protective features and cause apoptosis. In normal cells and tissues ERX-41 does not induce ER stress, suggesting that the basal level of ER stress and the compensatory UPR pathway may dictate responsiveness to ERX-41.<a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a></p><p id="p0125" class="elsevierStylePara elsevierViewall">The researchers found that ERX-41 interacts to lysosomal acid lipase A, a biological protein (LIPA). The endoplasmic reticulum, an organelle that processes and folds proteins, is where LIPA is located in cells. Cancer cells greatly overproduce LIPA, much more so than healthy cells, which puts stress on the endoplasmic reticulum in order for the tumor cell to develop quickly. By attaching to LIPA, ERX-41 prevents the endoplasmic reticulum from properly digesting proteins, which causes the cell to die. When the chemical was given to mice that had malignant tumors similar to those found in humans, the tumors shrank. Other cancer forms with high endoplasmic reticulum stress are responsive to ERX-41, including glioblastoma, the most aggressive and deadly primary brain tumor, as well as the difficult-to-treat pancreatic and ovarian malignancies. In combination, ERX-41 targets LIPA in the ER, which causes ER stress in TNBC, and this has not yet been fully understood. Neither ERX-41 nor the LAL lipase function are necessary for ERX-41 action.</p></span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">Conclusion</span><p id="p0130" class="elsevierStylePara elsevierViewall">Finally, ERX-41 is a robust therapeutic drug with a well-defined molecular target (LAL) and mode of action (disruption of protein folding and production of ER stress) that may be useful in treating patients with numerous solid cancers. The lipase function of LAL is neither affected by ERX-41 nor is critical for ERX-41 activity. In conclusion, ERX-41 is a potent therapeutic agent with a clear molecular target (LAL) and mechanism of action (disruption of protein folding and induction of ER stress) that may have utility in treating patients with multiple solid tumors.</p></span><span id="s0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0090">Ethics approval</span><p id="p0135" class="elsevierStylePara elsevierViewall">The manuscript is a review article and none to declare ethics approval.</p></span><span id="s0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0095">Consent to participate</span><p id="p0140" class="elsevierStylePara elsevierViewall">Informed consent was obtained from all individual participants included in the study.</p></span><span id="s0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0100">Consent for publication</span><p id="p0145" class="elsevierStylePara elsevierViewall">Informed consent was obtained from all individual participants for whom identifying information is included in this article.</p></span><span id="s0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0105">Availability of data and material</span><p id="p0150" class="elsevierStylePara elsevierViewall">The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.</p></span><span id="s0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0110">Code availability</span><p id="p0155" class="elsevierStylePara elsevierViewall">Not applicable.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:23 [ 0 => array:3 [ "identificador" => "xres2078650" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1773363" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2078649" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1773364" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "s0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "s0010" "titulo" => "ER STRESS induction and unfolded protein response" ] 6 => array:2 [ "identificador" => "s0015" "titulo" => "Signaling pathways related to ERS and UPR" ] 7 => array:2 [ "identificador" => "s0020" "titulo" => "ER stress-mediated apoptosis in chronic or excessive conditions" ] 8 => array:2 [ "identificador" => "s0025" "titulo" => "ER-targeting based on many approaches" ] 9 => array:2 [ "identificador" => "s0030" "titulo" => "Small molecules" ] 10 => array:2 [ "identificador" => "s0035" "titulo" => "ERX-41: a novel small molecule target medication" ] 11 => array:2 [ "identificador" => "s0040" "titulo" => "LIPA structure and functions" ] 12 => array:2 [ "identificador" => "s0045" "titulo" => "LAL protein's lysosomal subcellular location is related to its function as a LIPA" ] 13 => array:2 [ "identificador" => "s0050" "titulo" => "Protein folding in the ER is disturbed by ERX-41's induction of ER stress" ] 14 => array:2 [ "identificador" => "s0055" "titulo" => "Targeting LIPA in TNBC and solid tumors" ] 15 => array:2 [ "identificador" => "s0060" "titulo" => "Discussion" ] 16 => array:2 [ "identificador" => "s0065" "titulo" => "Conclusion" ] 17 => array:2 [ "identificador" => "s0070" "titulo" => "Ethics approval" ] 18 => array:2 [ "identificador" => "s0075" "titulo" => "Consent to participate" ] 19 => array:2 [ "identificador" => "s0080" "titulo" => "Consent for publication" ] 20 => array:2 [ "identificador" => "s0085" "titulo" => "Availability of data and material" ] 21 => array:2 [ "identificador" => "s0090" "titulo" => "Code availability" ] 22 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-03-16" "fechaAceptado" => "2023-06-01" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1773363" "palabras" => array:5 [ 0 => "Cancer" 1 => "ER stress" 2 => "ERX-41" 3 => "LIPA" 4 => "Small molecule" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1773364" "palabras" => array:5 [ 0 => "cáncer" 1 => "estrés ER" 2 => "ERX-41" 3 => "LIPA" 4 => "molécula pequeña" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Recently there has been an incredible shift in cancer treatment, from broad-spectrum cytotoxic drugs to targeted drugs known as small molecules and macromolecules. Although traditional therapies have been effective in cancer treatment, they often have adverse side effects due to their nonspecific action on both normal and tumor cells. The endoplasmic reticulum (ER), is known to control a variety of vital cellular processes, including protein production, folding/misfolding, and unfolding. The ER affects cell survival and death by activating the unfolded protein response (UPR) if the balance is not preserved. Dysregulation of these pathways' homeostasis in the ER is consequently linked to the emergence and development of cancer's pathological states. Therefore, targeting ER stress and ER stress-mediated apoptosis in cancer cells by small-molecule emerged as an intriguing unconventional approach that may be an effective strategy for treating cancers. This review attempts to introduce one of the newest small molecules known as ERX-41 for cancer has a poor clinical outcome strategy for solid tumors, including breast, brain, pancreatic and ovarian cancer. ERX-41 induces ER stress resulting in cell death through specific LIPA targeting. Importantly, demonstrated that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding and induce ER stress. This molecules targeted approach has a large therapeutic window, with no adverse effects either on normal cells and leading of new Achilles heel discovery in the therapeutics development for multiple hard-to-treat solid tumors.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Recientemente ha habido un cambio increíble en el tratamiento del cáncer, de fármacos citotóxicos de amplio espectro a fármacos dirigidos conocidos como moléculas pequeñas y macromoléculas. Aunque las terapias tradicionales han sido efectivas en el tratamiento del cáncer, a menudo tienen efectos secundarios adversos debido a su acción inespecífica tanto en las células normales como en las tumorales. Se sabe que el retículo endoplásmico (RE) controla una variedad de procesos celulares vitales, incluida la producción de proteínas, el plegamiento/mal plegamiento y el despliegue. El RE afecta la supervivencia y muerte celular al activar la respuesta de proteína desplegada (UPR) si no se conserva el equilibrio. La desregulación de la homeostasis de estas vías en la sala de emergencias está, en consecuencia, relacionada con la aparición y el desarrollo de los estados patológicos del cáncer. Por lo tanto, abordar el estrés del ER y la apoptosis mediada por el estrés del ER en las células cancerosas mediante moléculas pequeñas surgió como un enfoque no convencional intrigante que puede ser una estrategia eficaz para tratar el cáncer. Esta revisión intenta presentar una de las moléculas pequeñas más nuevas conocida como ERX-41 para el cáncer que tiene una estrategia de resultados clínicos deficientes para los tumores sólidos, incluidos el cáncer de mama, cerebro, páncreas y ovario. ERX-41 induce estrés ER que resulta en la muerte celular a través de la orientación específica de LIPA. Es importante destacar que demostró que la actividad de ERX-41 es independiente de la función de la lipasa LIPA pero depende de su localización en el RE. De manera mecánica, la unión de ERX-41 a LIPA disminuye la expresión de múltiples proteínas residentes en ER involucradas en el plegamiento de proteínas e induce estrés en ER. Este enfoque dirigido a moléculas tiene una gran ventana terapéutica, sin efectos adversos en las células normales y liderando el descubrimiento de un nuevo talón de Aquiles en el desarrollo de terapias para múltiples tumores sólidos difíciles de tratar.</p></span>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "f0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1929 "Ancho" => 2756 "Tamanyo" => 550649 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Endoplasmic reticulum (ER) stress (ERS) and unfolded protein response (UPR) signaling. Cancer cells are frequently subjected to extrinsic and internal stressors that affect protein folding in the ER. UPR signaling is coordinated by three ERS sensors (IRE1, PERK, and ATF6). Bip (GRP78) is normally connected to ERS sensors, leaving them inactive. Bip (GRP78) detaches from the three transmembrane proteins on the ER membrane and activates these pathways during ERS. Stimuli that cause an increase or accumulation of unfolded or misfolded proteins in the ER luz will cause a shift in the “Bip equilibrium,” resulting in the dissociation of this factor from the three ER stress sensors and an increase in the levels of free Bip (GRP78) to be used as a chaperone. When PERK was activated, the cytosolic domain dimerized and autophosphorylated. PERK phosphorylation of eIF2a decreases overall protein synthesis while promoting ATF4 mRNA translation. The endoribonuclease domain of IRE1 is activated via dimerization and autophosphorylation. Following IRE1 activation, unspliced XBP1 u mRNA is processed, and spliced XBP1s mRNA is translated into an active transcription factor. ATF6 is activated and translocated to the Golgi apparatus, where it is cleaved by site 1 and site 2 proteases (S1P and S2P) and translocate to the nucleus. The IRE1, PERK, and ATF6 pathways work together to control numerous genes in order to restore ER homeostasis and drive survival, angiogenesis, metastasis, and cell death resistance in cancer. ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; ER, endoplasmic reticulum; eIF2α, eukaryotic initiation factor 2α; GRP78, glucose-regulated protein 78; IRE1α, inositol-requiring enzyme 1; P, phosphorylation; PERK, protein kinase-like ER kinase; RIDD, regulated IRE1α-dependent decay; S1P, Site1 Protease; S2P, Site2 Protease; XBP-1 s, spliced X-box binding protein 1; and XBP-1u, unspliced X-box binding protein 1.</p>" ] ] 1 => array:8 [ "identificador" => "f0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1929 "Ancho" => 2756 "Tamanyo" => 537865 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">ERX-41 binds LAL and is independent of lipase activity. 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