Pub Date : 2024-11-14DOI: 10.1016/j.bbamcr.2024.119876
Eléa A. Renaud, Ambre J.M. Maupin, Sébastien Besteiro
Iron‑sulfur cluster are ubiquitous and ancient protein cofactors that support a wide array of essential cellular functions. In eukaryotes, their assembly requires specific and dedicated machineries in each subcellular compartment. Apicomplexans are parasitic protists that are collectively responsible for a significant burden on the health of humans and other animals, and most of them harbor two organelles of endosymbiotic origin: a mitochondrion, and a plastid of high metabolic importance called the apicoplast. Consequently, apicomplexan parasites have distinct iron‑sulfur cluster assembly machineries located to their endosymbiotic organelles, as well as a cytosolic pathway. Recent findings have not only shown the importance of iron‑sulfur cluster assembly for the fitness of these parasites, but also highlighted parasite-specific features that may be promising for the development of targeted anti-parasitic strategies.
{"title":"Iron‑sulfur cluster biogenesis and function in Apicomplexa parasites","authors":"Eléa A. Renaud, Ambre J.M. Maupin, Sébastien Besteiro","doi":"10.1016/j.bbamcr.2024.119876","DOIUrl":"10.1016/j.bbamcr.2024.119876","url":null,"abstract":"<div><div>Iron‑sulfur cluster are ubiquitous and ancient protein cofactors that support a wide array of essential cellular functions. In eukaryotes, their assembly requires specific and dedicated machineries in each subcellular compartment. Apicomplexans are parasitic protists that are collectively responsible for a significant burden on the health of humans and other animals, and most of them harbor two organelles of endosymbiotic origin: a mitochondrion, and a plastid of high metabolic importance called the apicoplast. Consequently, apicomplexan parasites have distinct iron‑sulfur cluster assembly machineries located to their endosymbiotic organelles, as well as a cytosolic pathway. Recent findings have not only shown the importance of iron‑sulfur cluster assembly for the fitness of these parasites, but also highlighted parasite-specific features that may be promising for the development of targeted anti-parasitic strategies.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119876"},"PeriodicalIF":4.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.bbamcr.2024.119875
Khushboo Sharma , Pooja Rai , Madhu G. Tapadia
Compelling evidence has strongly linked unregulated sugar levels to developing Alzheimer's disease, suggesting Alzheimer's to be ‘diabetes of the brain or ‘type 3 diabetes. Insulin resistance contributes to the pathogenesis of Alzheimer's disease due to uncontrolled and unchecked blood glucose, though the interrelatedness between Alzheimer's disease and type 2 diabetes is debatable. Here we describe the consequences of inducing type 3 diabetes by feeding Drosophila on a high sucrose diet, which effectively mimics the pathophysiology of diabetes. A high sucrose diet increases glycogen and lipid accumulation. Inducing type 3 diabetes worsened neurodegeneration and accelerated disease progression in Drosophila expressing the Alzheimer's Familial Arctic mutation. High sucrose milieu also negatively affected locomotor ability and reduced the lifespan in the Alzheimer's disease model of Drosophila. The results showed that creating diabetic conditions by using insulin receptor (InR) knockdown in the eyes of Drosophila led to a degenerative phenotype, indicating a genetic interaction between the insulin signaling pathway and Alzheimer's disease. The expression of PERK reflects disruption in the endoplasmic reticulum homeostasis due to amyloid-β (Aβ) under a high sucrose diet. These observations demonstrated an association between type 3 diabetes and Alzheimer's disease, and that a high sucrose environment has a degenerating effect on Alzheimer's disease condition.
{"title":"Impaired insulin signaling and diet-induced type 3 diabetes pathophysiology increase amyloid β expression in the Drosophila model of Alzheimer's disease","authors":"Khushboo Sharma , Pooja Rai , Madhu G. Tapadia","doi":"10.1016/j.bbamcr.2024.119875","DOIUrl":"10.1016/j.bbamcr.2024.119875","url":null,"abstract":"<div><div>Compelling evidence has strongly linked unregulated sugar levels to developing Alzheimer's disease, suggesting Alzheimer's to be ‘diabetes of the brain or ‘type 3 diabetes. Insulin resistance contributes to the pathogenesis of Alzheimer's disease due to uncontrolled and unchecked blood glucose, though the interrelatedness between Alzheimer's disease and type 2 diabetes is debatable. Here we describe the consequences of inducing type 3 diabetes by feeding <em>Drosophila</em> on a high sucrose diet, which effectively mimics the pathophysiology of diabetes. A high sucrose diet increases glycogen and lipid accumulation. Inducing type 3 diabetes worsened neurodegeneration and accelerated disease progression in <em>Drosophila</em> expressing the Alzheimer's Familial Arctic mutation. High sucrose milieu also negatively affected locomotor ability and reduced the lifespan in the Alzheimer's disease model of <em>Drosophila</em>. The results showed that creating diabetic conditions by using insulin receptor (InR) knockdown in the eyes of <em>Drosophila</em> led to a degenerative phenotype, indicating a genetic interaction between the insulin signaling pathway and Alzheimer's disease. The expression of PERK reflects disruption in the endoplasmic reticulum homeostasis due to amyloid-β (Aβ) under a high sucrose diet. These observations demonstrated an association between type 3 diabetes and Alzheimer's disease, and that a high sucrose environment has a degenerating effect on Alzheimer's disease condition.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119875"},"PeriodicalIF":4.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.bbamcr.2024.119874
A. Falconieri
The interactions between mechanical forces and neuronal dynamics have long intrigued researchers. Several studies revealed that force plays a pivotal role in shaping axonal outgrowth. However, the molecular mechanisms underpinning force-driven axonal plasticity remain not completely elucidated. This review explores the relationship between force and axonal plasticity, with a focus on local mechanisms, including local translation and axonal transport, and the emerging concept of force-driven cross-talk, a dialogue in which local dynamics are tightly regulated. Recent experimental evidence suggests that microtubules may serve as key mediators of this cross-talk, orchestrating the coordination between local mechanisms and facilitating mass addition.
{"title":"Interplay of force and local mechanisms in axonal plasticity and beyond","authors":"A. Falconieri","doi":"10.1016/j.bbamcr.2024.119874","DOIUrl":"10.1016/j.bbamcr.2024.119874","url":null,"abstract":"<div><div>The interactions between mechanical forces and neuronal dynamics have long intrigued researchers. Several studies revealed that force plays a pivotal role in shaping axonal outgrowth. However, the molecular mechanisms underpinning force-driven axonal plasticity remain not completely elucidated. This review explores the relationship between force and axonal plasticity, with a focus on local mechanisms, including local translation and axonal transport, and the emerging concept of force-driven cross-talk, a dialogue in which local dynamics are tightly regulated. Recent experimental evidence suggests that microtubules may serve as key mediators of this cross-talk, orchestrating the coordination between local mechanisms and facilitating mass addition.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119874"},"PeriodicalIF":4.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-06DOI: 10.1016/j.bbamcr.2024.119872
Anabela Ferreira , Stéphen Manon , Akandé Rouchidane Eyitayo , Susana R. Chaves , Manuela Côrte-Real , Ana Preto , Maria João Sousa
Kirsten rat sarcoma viral oncogene homolog (KRAS) belongs to the GTPase RAS superfamily, which regulates several cell-signaling pathways involved in the control of important cellular functions, including apoptosis. Oncogenic mutations in KRAS are considered the most common gain-of-function mutations, affecting 30–50 % of colorectal cancer (CRC) patients. While RAS proteins usually play an anti-apoptotic role, little is known about the involvement of KRAS mutations in apoptosis regulation. Here, we aimed to elucidate the role of mutated human KRAS in the regulation of BAX, a key pro-apoptotic member of the Bcl-2 family. For this purpose, we took advantage of the simpler yeast model Saccharomyces cerevisiae, using cells deficient in the main yeast RAS isoform (ras2Δ) co-expressing wild-type KRAS (KRASWT) or the most frequent KRAS mutations found in CRC - KRASG12D, KRASG12V or KRASG13D, along with human BAX. We show that, in comparison with KRASWT, KRAS mutants confer resistance to BAX-induced death and cytochrome c (cyt c) release. The modulation of BAX by KRAS isoforms seems to result from a direct interaction between these proteins, as they co-localize at the mitochondria and there is evidence they may physically interact. We further show that acetic acid significantly increased cell death in cells expressing BAX and co-expressing oncogenic KRAS mutants, but not KRASWT. This suggests a potential mechanism explaining the increased sensitivity of CRC cells harboring a KRAS-activated pathway to acetate. These findings contribute to a clearer understanding of how KRAS regulate BAX function, a relevant aspect in tumor progression.
{"title":"Oncogenic KRAS mutations modulate BAX-mediated cell death","authors":"Anabela Ferreira , Stéphen Manon , Akandé Rouchidane Eyitayo , Susana R. Chaves , Manuela Côrte-Real , Ana Preto , Maria João Sousa","doi":"10.1016/j.bbamcr.2024.119872","DOIUrl":"10.1016/j.bbamcr.2024.119872","url":null,"abstract":"<div><div>Kirsten rat sarcoma viral oncogene homolog (KRAS) belongs to the GTPase RAS superfamily, which regulates several cell-signaling pathways involved in the control of important cellular functions, including apoptosis. Oncogenic mutations in KRAS are considered the most common gain-of-function mutations, affecting 30–50 % of colorectal cancer (CRC) patients. While RAS proteins usually play an anti-apoptotic role, little is known about the involvement of KRAS mutations in apoptosis regulation. Here, we aimed to elucidate the role of mutated human KRAS in the regulation of BAX, a key pro-apoptotic member of the Bcl-2 family. For this purpose, we took advantage of the simpler yeast model <em>Saccharomyces cerevisiae</em>, using cells deficient in the main yeast RAS isoform (<em>ras2</em>Δ) co-expressing wild-type KRAS (KRAS<sup>WT</sup>) or the most frequent KRAS mutations found in CRC - KRAS<sup>G12D</sup>, KRAS<sup>G12V</sup> or KRAS<sup>G13D</sup>, along with human BAX. We show that, in comparison with KRAS<sup>WT</sup>, KRAS mutants confer resistance to BAX-induced death and cytochrome <em>c</em> (cyt <em>c</em>) release. The modulation of BAX by KRAS isoforms seems to result from a direct interaction between these proteins, as they co-localize at the mitochondria and there is evidence they may physically interact. We further show that acetic acid significantly increased cell death in cells expressing BAX and co-expressing oncogenic KRAS mutants, but not KRAS<sup>WT</sup>. This suggests a potential mechanism explaining the increased sensitivity of CRC cells harboring a KRAS-activated pathway to acetate. These findings contribute to a clearer understanding of how KRAS regulate BAX function, a relevant aspect in tumor progression.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119872"},"PeriodicalIF":4.6,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-03DOI: 10.1016/j.bbamcr.2024.119873
Da Eun Lee , Hae Min Lee , Yunhyeok Jun , Soo Young Choi , Su Jin Lee , Oh-Shin Kwon
Resistance to chemotherapy drugs, which commonly occurs during the treatment of colorectal cancer (CRC), can lead to tumor recurrence and metastasis, so combinational treatment strategies according to the cancer cell type are urgently needed to overcome drug resistance and increase therapeutic efficiency. To this end, the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer strategy. Some CRC cell lines such as SW620 have low sensitivity to TRAIL, so additional sensitizers are required to make the strategy effective. Therefore, we focused on the apoptotic effect of combinational metformin and TRAIL treatment on TRAIL-resistant SW620 cells. Treatment with TRAIL alone did not induce apoptosis whereas combined treatment with metformin and TRAIL significantly increased it. TRAIL activated caspases through an extrinsic pathway but increased resistance to apoptosis through the protein kinase B or AKT (PKB/AKT)/mammalian target of rapamycin (mTOR) pathway. On the other hand, metformin reduced the inhibitory effect of X-linked inhibitor of apoptosis (XIAP) by blocking the AKT and nuclear factor kappa B (NF-κB) pathways and activated CCAAT-enhancer-binding protein homologous protein (CHOP) via endoplasmic reticulum (ER) stress but without inducing apoptosis. In addition, metformin induced cell-cycle arrest, thereby blocking cell proliferation and growth. These results were also confirmed through an in vivo mouse xenograft CRC model, in which combined treatment with metformin and TRAIL induced tumor cell death, thus demonstrating the anticancer effect of their coadministration. Therefore, cotreatment of metformin and TRAIL could be an effective anticancer treatment strategy for TRAIL-resistant CRC.
{"title":"Metformin induces apoptosis in TRAIL-resistant colorectal cancer cells","authors":"Da Eun Lee , Hae Min Lee , Yunhyeok Jun , Soo Young Choi , Su Jin Lee , Oh-Shin Kwon","doi":"10.1016/j.bbamcr.2024.119873","DOIUrl":"10.1016/j.bbamcr.2024.119873","url":null,"abstract":"<div><div>Resistance to chemotherapy drugs, which commonly occurs during the treatment of colorectal cancer (CRC), can lead to tumor recurrence and metastasis, so combinational treatment strategies according to the cancer cell type are urgently needed to overcome drug resistance and increase therapeutic efficiency. To this end, the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer strategy. Some CRC cell lines such as SW620 have low sensitivity to TRAIL, so additional sensitizers are required to make the strategy effective. Therefore, we focused on the apoptotic effect of combinational metformin and TRAIL treatment on TRAIL-resistant SW620 cells. Treatment with TRAIL alone did not induce apoptosis whereas combined treatment with metformin and TRAIL significantly increased it. TRAIL activated caspases through an extrinsic pathway but increased resistance to apoptosis through the protein kinase B or AKT (PKB/AKT)/mammalian target of rapamycin (mTOR) pathway. On the other hand, metformin reduced the inhibitory effect of X-linked inhibitor of apoptosis (XIAP) by blocking the AKT and nuclear factor kappa B (NF-κB) pathways and activated CCAAT-enhancer-binding protein homologous protein (CHOP) via endoplasmic reticulum (ER) stress but without inducing apoptosis. In addition, metformin induced cell-cycle arrest, thereby blocking cell proliferation and growth. These results were also confirmed through an in vivo mouse xenograft CRC model, in which combined treatment with metformin and TRAIL induced tumor cell death, thus demonstrating the anticancer effect of their coadministration. Therefore, cotreatment of metformin and TRAIL could be an effective anticancer treatment strategy for TRAIL-resistant CRC.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119873"},"PeriodicalIF":4.6,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1016/j.bbamcr.2024.119870
Zhangji Dong , Qing Wang , Yingying Yan , Liang Oscar Qiang , Mei Liu
The Fidgetin (FIGN) family, which comprises FIGN, Fidgetin-like 1 (FIGNL1), and Fidgetin-like 2 (FIGNL2), is a vital group of microtubule-severing proteins. These proteins feature a conserved AAA+ domain essential for ATPase activity and a hexameric assembly. This review provides an in-depth analysis of the evolution and functional divergence of the FIGN family members, highlighting their role in the dynamic organization of the cytoskeleton. We further explore their broader biological functions across various species, systems, and subcellular localization. Although the FIGN family is conserved, each member exhibits unique structural characteristics and functions that reflect their evolutionary adaptations. FIGNL1 is found across animal species, while FIGNL2 is specific to vertebrates, thereby indicating its more recent evolutionary origin. Moreover, synteny analysis has revealed that FIGN is located in a more conserved genomic region compared to FIGNL2, which has undergone substantial evolutionary changes. The expression patterns of the FIGN members also vary across organisms and tissues. For example, FIGNL2 shows a notably reduced expression in the mammalian nervous system compared to that in lower vertebrates. The FIGN family members have distinct roles in microtubule severing, cell division, and DNA repair. Specifically, FIGN is involved in cell division and neuronal regeneration, FIGNL1 in axonal growth and DNA repair, and FIGNL2 in cell migration and vascular development. Their involvement in these processes underscores their role as potential biomarkers for certain cancers as well as therapeutic targets for diseases affecting the nervous system and cardiovascular development. All these evolutionary insights and functional distinctions of the FIGN family offer a comprehensive framework for understanding cytoskeletal regulation and its implications in health and disease.
{"title":"Evolution and functional divergence of the Fidgetin family","authors":"Zhangji Dong , Qing Wang , Yingying Yan , Liang Oscar Qiang , Mei Liu","doi":"10.1016/j.bbamcr.2024.119870","DOIUrl":"10.1016/j.bbamcr.2024.119870","url":null,"abstract":"<div><div>The Fidgetin (FIGN) family, which comprises FIGN, Fidgetin-like 1 (FIGNL1), and Fidgetin-like 2 (FIGNL2), is a vital group of microtubule-severing proteins. These proteins feature a conserved AAA+ domain essential for ATPase activity and a hexameric assembly. This review provides an in-depth analysis of the evolution and functional divergence of the FIGN family members, highlighting their role in the dynamic organization of the cytoskeleton. We further explore their broader biological functions across various species, systems, and subcellular localization. Although the FIGN family is conserved, each member exhibits unique structural characteristics and functions that reflect their evolutionary adaptations. FIGNL1 is found across animal species, while FIGNL2 is specific to vertebrates, thereby indicating its more recent evolutionary origin. Moreover, synteny analysis has revealed that FIGN is located in a more conserved genomic region compared to FIGNL2, which has undergone substantial evolutionary changes. The expression patterns of the FIGN members also vary across organisms and tissues. For example, FIGNL2 shows a notably reduced expression in the mammalian nervous system compared to that in lower vertebrates. The FIGN family members have distinct roles in microtubule severing, cell division, and DNA repair. Specifically, FIGN is involved in cell division and neuronal regeneration, FIGNL1 in axonal growth and DNA repair, and FIGNL2 in cell migration and vascular development. Their involvement in these processes underscores their role as potential biomarkers for certain cancers as well as therapeutic targets for diseases affecting the nervous system and cardiovascular development. All these evolutionary insights and functional distinctions of the FIGN family offer a comprehensive framework for understanding cytoskeletal regulation and its implications in health and disease.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119870"},"PeriodicalIF":4.6,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The significance of physical factors in the onset and progression of tumors has been increasingly substantiated by a multitude of studies. The extracellular matrix, a pivotal component of the tumor microenvironment, has been the subject of extensive investigation in connection with the advancement of KIRC (Kidney Renal Clear Cell Carcinoma) in recent years. PIEZO1, a mechanosensitive ion channel, has been recognized as a modulator of diverse physiological processes. Nonetheless, the precise function of PIEZO1 as a transducer of mechanical stimuli in KIRC remains poorly elucidated.
Methods
A bioinformatics analysis was conducted using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) to explore the correlation between matrix stiffness indicators, such as COL1A1 and LOX mRNA levels, and KIRC prognosis. Expression patterns of mechanosensitive ion channels, particularly PIEZO1, were examined. Collagen-coated polyacrylamide hydrogel models were utilized to simulate varying stiffness environments and study their effects on KIRC cell behavior in vitro. Functional experiments, including PIEZO1 knockdown and overexpression, were performed to investigate the molecular mechanisms underlying matrix stiffness-induced cellular changes. Interventions in the Ca2+/Calpain/YAP Pathway were conducted to evaluate their effects on cell growth, EMT, and stemness characteristics.
Results
Our findings indicate a significant correlation between matrix stiffness and the prognosis of KIRC patients. It is observed that higher mechanical stiffness can facilitate the growth and metastasis of KIRC cells. Notably, we have also observed that the deficiency of PIEZO1 hinders the proliferation, EMT, and stemness characteristics of KIRC cells induced by a stiff matrix. Our study suggests that PIEZO1 plays a crucial role in mediating KIRC growth and metastasis through the activation of the Ca2+/Calpain/YAP Pathway.
Conclusion
This study elucidates a novel mechanism through which the activation of PIEZO1 leads to calcium influx, subsequent calpain activation, and YAP nuclear translocation, thereby contributing to the progression of KIRC driven by matrix stiffness.
{"title":"PIEZO1 mediates matrix stiffness-induced tumor progression in kidney renal clear cell carcinoma by activating the Ca2+/Calpain/YAP pathway","authors":"Biqiang Zhu , Fan Li , Jiajun Yu, Zhulin Liang, Xinwen Ke, Yong Wang, Zhengshuai Song, Zhongyuan Li, Guohao Li, Yonglian Guo","doi":"10.1016/j.bbamcr.2024.119871","DOIUrl":"10.1016/j.bbamcr.2024.119871","url":null,"abstract":"<div><h3>Objective</h3><div>The significance of physical factors in the onset and progression of tumors has been increasingly substantiated by a multitude of studies. The extracellular matrix, a pivotal component of the tumor microenvironment, has been the subject of extensive investigation in connection with the advancement of KIRC (Kidney Renal Clear Cell Carcinoma) in recent years. PIEZO1, a mechanosensitive ion channel, has been recognized as a modulator of diverse physiological processes. Nonetheless, the precise function of PIEZO1 as a transducer of mechanical stimuli in KIRC remains poorly elucidated.</div></div><div><h3>Methods</h3><div>A bioinformatics analysis was conducted using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) to explore the correlation between matrix stiffness indicators, such as COL1A1 and LOX mRNA levels, and KIRC prognosis. Expression patterns of mechanosensitive ion channels, particularly PIEZO1, were examined. Collagen-coated polyacrylamide hydrogel models were utilized to simulate varying stiffness environments and study their effects on KIRC cell behavior in vitro. Functional experiments, including PIEZO1 knockdown and overexpression, were performed to investigate the molecular mechanisms underlying matrix stiffness-induced cellular changes. Interventions in the Ca2<sup>+</sup>/Calpain/YAP Pathway were conducted to evaluate their effects on cell growth, EMT, and stemness characteristics.</div></div><div><h3>Results</h3><div>Our findings indicate a significant correlation between matrix stiffness and the prognosis of KIRC patients. It is observed that higher mechanical stiffness can facilitate the growth and metastasis of KIRC cells. Notably, we have also observed that the deficiency of PIEZO1 hinders the proliferation, EMT, and stemness characteristics of KIRC cells induced by a stiff matrix. Our study suggests that PIEZO1 plays a crucial role in mediating KIRC growth and metastasis through the activation of the Ca<sup>2+</sup>/Calpain/YAP Pathway.</div></div><div><h3>Conclusion</h3><div>This study elucidates a novel mechanism through which the activation of PIEZO1 leads to calcium influx, subsequent calpain activation, and YAP nuclear translocation, thereby contributing to the progression of KIRC driven by matrix stiffness.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119871"},"PeriodicalIF":4.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-26DOI: 10.1016/j.bbamcr.2024.119869
Haitang Liao , Shuang Liu , Qiang Ma , He Huang , Arul Goel , Pedram Torabian , Chakrabhavi Dhananjaya Mohan , Chenyang Duan
The endoplasmic reticulum (ER) is a dynamic organelle that is a site of the synthesis of proteins and lipids, contributing to the regulation of proteostasis, lipid metabolism, redox balance, and calcium storage/−dependent signaling events. The disruption of ER homeostasis due to the accumulation of misfolded proteins in the ER causes ER stress which activates the unfolded protein response (UPR) system through the activation of IRE1, PERK, and ATF6. Activation of UPR is observed in various cancers and therefore, its association with process of carcinogenesis has been of importance. Tumor cells effectively utilize the UPR system to overcome ER stress. Moreover, ER stress and autophagy are the stress response mechanisms operating together to maintain cellular homeostasis. In human cancers, ER stress-driven autophagy can function as either pro-survival or pro-death in a context-dependent manner. ER stress-mediated autophagy can have crosstalk with other types of cell death pathways including apoptosis and ferroptosis. In this connection, the present review has evaluated the role of ER stress in the regulation of autophagy-mediated tumorigenesis and its interactions with other cell death mechanisms such as apoptosis and ferroptosis. We have also comprehensively discussed the effect of ER stress-mediated autophagy on cancer progression and chemotherapeutic resistance.
内质网（ER）是一个动态细胞器，是合成蛋白质和脂质的场所，并参与调节蛋白稳态、脂质代谢、氧化还原平衡和钙储存/依赖信号事件。ER中错误折叠蛋白的积累导致ER平衡的破坏，从而引起ER应激，并通过激活IRE1、PERK和ATF6激活未折叠蛋白反应（UPR）系统。在各种癌症中都能观察到 UPR 的激活，肿瘤细胞能有效利用 UPR 系统克服 ER 压力。此外，ER 应激和自噬是共同维持细胞平衡的应激反应机制。在癌症中，ER应激介导的自噬可根据具体情况发挥促生存或促死亡的作用。ER应激介导的自噬可与其他类型的细胞死亡途径（包括细胞凋亡和铁凋亡）相互影响。在这篇文章中，我们回顾了ER应激在自噬介导的肿瘤发生调控中的作用及其与细胞凋亡和铁凋亡等其他细胞死亡机制的相互作用。我们还全面讨论了ER应激介导的自噬对癌症进展和化疗耐药性的影响。
{"title":"Endoplasmic reticulum stress induced autophagy in cancer and its potential interactions with apoptosis and ferroptosis","authors":"Haitang Liao , Shuang Liu , Qiang Ma , He Huang , Arul Goel , Pedram Torabian , Chakrabhavi Dhananjaya Mohan , Chenyang Duan","doi":"10.1016/j.bbamcr.2024.119869","DOIUrl":"10.1016/j.bbamcr.2024.119869","url":null,"abstract":"<div><div>The endoplasmic reticulum (ER) is a dynamic organelle that is a site of the synthesis of proteins and lipids, contributing to the regulation of proteostasis, lipid metabolism, redox balance, and calcium storage/−dependent signaling events. The disruption of ER homeostasis due to the accumulation of misfolded proteins in the ER causes ER stress which activates the unfolded protein response (UPR) system through the activation of IRE1, PERK, and ATF6. Activation of UPR is observed in various cancers and therefore, its association with process of carcinogenesis has been of importance. Tumor cells effectively utilize the UPR system to overcome ER stress. Moreover, ER stress and autophagy are the stress response mechanisms operating together to maintain cellular homeostasis. In human cancers, ER stress-driven autophagy can function as either pro-survival or pro-death in a context-dependent manner. ER stress-mediated autophagy can have crosstalk with other types of cell death pathways including apoptosis and ferroptosis. In this connection, the present review has evaluated the role of ER stress in the regulation of autophagy-mediated tumorigenesis and its interactions with other cell death mechanisms such as apoptosis and ferroptosis. We have also comprehensively discussed the effect of ER stress-mediated autophagy on cancer progression and chemotherapeutic resistance.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119869"},"PeriodicalIF":4.6,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-25DOI: 10.1016/j.bbamcr.2024.119868
Roland Lill, Frederic Barras
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Pub Date : 2024-10-21DOI: 10.1016/j.bbamcr.2024.119866
Fernando D. Gomez , Julieta Reppetti , Romina S. Alvarez , Daniel C. Girón Reyes , Flavia Sacerdoti , Alejandro Balestracci , Alicia E. Damiano , Nora A. Martínez , Gisela Di Giusto , María M. Amaral
One of the hallmarks of Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is kidney damage. Our previous research demonstrated that Shiga toxin type 2 (Stx2a) decreases cell viability and induces swelling of human glomerular endothelial cells (HGEC). However, Stx2a can disrupt net water transport across HGEC monolayers without affecting cell viability. This work aimed to elucidate the possible mechanisms involved in the water transport disruption caused by Stx2a across HGEC monolayers. We investigated paracellular and transcellular water transfer across HGEC by analyzing the passage of FITC-Dextran and the hydrostatic pressure (Phydr) and measuring the osmotic pressure (Posm), respectively. Stx2a selectively affected the transcellular pathway without impacting the paracellular route. Furthermore, Stx2a cell swelling was prevented by pretreatment with aquaporin inhibitors tetraethylammonium chloride (TEA), Mercury (II) chloride (HgCl2) or TGN-020, suggesting aquaporin involvement in this process. Confocal microscopy revealed that Stx2a increased HGEC total volume, which TEA and TGN-020 counteracted. Additionally, we identified in HGEC not only the expression of aquaporin-1 (AQP1) but also the expression of aquaporin-4 (AQP4). Surprisingly, we observed a decrease in the expression of both AQPs after Stx2a exposure. Our findings suggest that Stx2a may induce water movement into HGEC via AQP1 and AQP4, increasing total cell volume. Subsequently, decreased AQP1 and AQP4 expression could inhibit transcellular water transfer, potentially as a protective mechanism against excessive water entry and cell lysis.
{"title":"Involvement of aquaporins in Shiga toxin-induced swelling and water transport dysfunction in human renal microvascular endothelial cells","authors":"Fernando D. Gomez , Julieta Reppetti , Romina S. Alvarez , Daniel C. Girón Reyes , Flavia Sacerdoti , Alejandro Balestracci , Alicia E. Damiano , Nora A. Martínez , Gisela Di Giusto , María M. Amaral","doi":"10.1016/j.bbamcr.2024.119866","DOIUrl":"10.1016/j.bbamcr.2024.119866","url":null,"abstract":"<div><div>One of the hallmarks of Shiga toxin-producing <em>Escherichia coli</em>-associated hemolytic uremic syndrome (STEC-HUS) is kidney damage. Our previous research demonstrated that Shiga toxin type 2 (Stx2a) decreases cell viability and induces swelling of human glomerular endothelial cells (HGEC). However, Stx2a can disrupt net water transport across HGEC monolayers without affecting cell viability. This work aimed to elucidate the possible mechanisms involved in the water transport disruption caused by Stx2a across HGEC monolayers. We investigated paracellular and transcellular water transfer across HGEC by analyzing the passage of FITC-Dextran and the hydrostatic pressure (Phydr) and measuring the osmotic pressure (Posm), respectively. Stx2a selectively affected the transcellular pathway without impacting the paracellular route. Furthermore, Stx2a cell swelling was prevented by pretreatment with aquaporin inhibitors tetraethylammonium chloride (TEA), Mercury (II) chloride (HgCl<sub>2</sub>) or TGN-020, suggesting aquaporin involvement in this process. Confocal microscopy revealed that Stx2a increased HGEC total volume, which TEA and TGN-020 counteracted. Additionally, we identified in HGEC not only the expression of aquaporin-1 (AQP1) but also the expression of aquaporin-4 (AQP4). Surprisingly, we observed a decrease in the expression of both AQPs after Stx2a exposure. Our findings suggest that Stx2a may induce water movement into HGEC via AQP1 and AQP4, increasing total cell volume. Subsequently, decreased AQP1 and AQP4 expression could inhibit transcellular water transfer, potentially as a protective mechanism against excessive water entry and cell lysis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119866"},"PeriodicalIF":4.6,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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