Cell StressPub Date : 2023-07-01DOI: 10.15698/cst2023.07.281
Andreas Zimmermann, Sebastian J Hofer, Frank Madeo
{"title":"Molecular targets of spermidine: implications for cancer suppression.","authors":"Andreas Zimmermann, Sebastian J Hofer, Frank Madeo","doi":"10.15698/cst2023.07.281","DOIUrl":"https://doi.org/10.15698/cst2023.07.281","url":null,"abstract":"<p><p>Spermidine is a ubiquitous, natural polyamine with geroprotective features. Supplementation of spermidine extends the lifespan of yeast, worms, flies, and mice, and dietary spermidine intake correlates with reduced human mortality. However, the crucial role of polyamines in cell proliferation has also implicated polyamine metabolism in neoplastic diseases, such as cancer. While depleting intracellular polyamine biosynthesis halts tumor growth in mouse models, lifelong external spermidine administration in mice does not increase cancer incidence. In contrast, a series of recent findings points to anti-neoplastic properties of spermidine administration in the context of immunotherapy. Various molecular mechanisms for the anti-aging and anti-cancer properties have been proposed, including the promotion of autophagy, enhanced translational control, and augmented mitochondrial function. For instance, spermidine allosterically activates mitochondrial trifunctional protein (MTP), a bipartite protein complex that mediates three of the four steps of mitochondrial fatty acid (β-oxidation. Through this action, spermidine supplementation is able to restore MTP-mediated mitochondrial respiratory capacity in naïve CD8<sup>+</sup> T cells to juvenile levels and thereby improves T cell activation in aged mice. Here, we put this finding into the context of the previously described molecular target space of spermidine.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9816794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell StressPub Date : 2023-06-01DOI: 10.15698/cst2023.06.280
Nermina Malanovic, Djenana Vejzovic
{"title":"Novel insights at the crossroads of antibiotic use and cancer risk.","authors":"Nermina Malanovic, Djenana Vejzovic","doi":"10.15698/cst2023.06.280","DOIUrl":"https://doi.org/10.15698/cst2023.06.280","url":null,"abstract":"<p><p>The continuous use of antibiotics is associated with the spread of antimicrobial resistances and the not yet clear link to cancer development. Many conventional antibiotics have already shown different effects on a variety of cancer types raising questions for their rational use in cancer. However, discrepancy in the observed trend for some antibiotics reducing cancer development and being associated with higher risk of cancer underscores the lack of understanding the complex link between antibiotics and cancer. Here, we briefly summarize the possible antibiotic-mediated effects on cancer and conclude that those effects can be direct via i) specific targeting of tumor/cancer, ii) antimicrobial activity and iii) immunomodulatory activity whereby iv) indirectly caused effects primarily affect immune equilibrium between bacteria, cancer and immune cells. Furthermore, we also conclude that there is a great need for bulk profiling, comprehensive screening programs in all countries and in-depth studies to understand the risks and benefits of antibiotic use.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9940007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell StressPub Date : 2023-05-01DOI: 10.15698/cst2023.05.279
Yulong Tang, Simeng Liao, Zhuyuan Nie, Guangwei Kuang, Chunxiao Ji, Dan Wan, Liuqin He, Fengna Li, Xiangfeng Kong, Kai Zhan, Bie Tan, Xin Wu, Yulong Yin
{"title":"CRISPR-activation screen identified potassium channels for protection against mycotoxins through cell cycle progression and mitochondrial function.","authors":"Yulong Tang, Simeng Liao, Zhuyuan Nie, Guangwei Kuang, Chunxiao Ji, Dan Wan, Liuqin He, Fengna Li, Xiangfeng Kong, Kai Zhan, Bie Tan, Xin Wu, Yulong Yin","doi":"10.15698/cst2023.05.279","DOIUrl":"https://doi.org/10.15698/cst2023.05.279","url":null,"abstract":"<p><p>Zearalenone (ZEA) exposure has carcinogenic effects on human and animal health by exhibiting intestinal, hepatic, and renal toxicity. At present, the underlying mechanisms on how ZEA induces apoptosis and damage to tissues still remain unclear. In this study, we aimed to identify genes that modulate the cellular response to ZEA using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening, and further validate novel gene functions to elucidate molecular mechanisms underlying particular biological processes <i>in vivo</i> and <i>in vitro</i>. Two ZEA-resistant cell lines, designated Ov-KCNJ4 and Ov-KCNJ12, were yielded by CRISPR activation screening which had significant changes in ZEA resistance and growth rates. Results showed that ZEA could interact with the cell membrane proteins <i>KCNJ4</i> and <i>KCNJ12</i>, inducing cell cycle arrest, disruption of DNA replication and base excision repair. Overexpression of <i>KCNJ4</i> and <i>KCNJ12</i> was involved in ZEA resistance by regulating cell cycle to neutralize toxicity, sustaining mitochondrial morphology and function via attenuating the damage from oxidative stress in the KCNJ4-mitoK<sub>ATP</sub> pathway. <i>In vivo</i> experiments showed that AAV-KCNJ4 delivery significantly improved ZEA-induced renal impairment and increased antioxidative enzyme activity by improving mitochondrial function. Our findings suggest that increasing potassium channel levels may be a putative therapeutic target for mycotoxin-induced damage.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10157994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9432533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell StressPub Date : 2023-04-01DOI: 10.15698/cst2023.04.278
Xin Yu, Ai-Ling Tian, Ping Wang, Juanjuan Li, Juan Wu, Bei Li, Zhou Liu, Siqing Liu, Zhijie Gao, Si Sun, Shengrong Sun, Yi Tu, Qi Wu
{"title":"Macrolide antibiotics activate the integrated stress response and promote tumor proliferation.","authors":"Xin Yu, Ai-Ling Tian, Ping Wang, Juanjuan Li, Juan Wu, Bei Li, Zhou Liu, Siqing Liu, Zhijie Gao, Si Sun, Shengrong Sun, Yi Tu, Qi Wu","doi":"10.15698/cst2023.04.278","DOIUrl":"https://doi.org/10.15698/cst2023.04.278","url":null,"abstract":"<p><p>Macrolide antibiotics are widely used antibacterial agents that are associated with autophagy inhibition. This study aimed to investigate the association between macrolide antibiotics and malignant tumors, as well as the effect on autophagy, reactive oxygen species (ROS) accumulation and integrated stress response (ISR). The meta-analysis indicated a modestly higher risk of cancer in macrolide antibiotic ever-users compared to non-users. Further experiments showed that macrolides block autophagic flux by inhibiting lysosomal acidification. Additionally, azithromycin, a representative macrolide antibiotic, induced the accumulation of ROS, and stimulated the ISR and the activation of transcription factor EB (TFEB) and TFE3 in a ROS-dependent manner. Finally, animal experiments confirmed that azithromycin promoted tumor progression <i>in vivo</i>, which could be receded by N-acetylcysteine, an inhibitor of ROS and ISR. Overall, this study reveals the potential role of macrolide antibiotics in malignant progression and highlights the need for further investigation into their effects.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10069438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9930702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell StressPub Date : 2023-03-01DOI: 10.15698/cst2023.03.277
Safae Terrisse, Laurence Zitvogel, Guido Kroemer
{"title":"Impact of microbiota on breast cancer hormone therapy.","authors":"Safae Terrisse, Laurence Zitvogel, Guido Kroemer","doi":"10.15698/cst2023.03.277","DOIUrl":"https://doi.org/10.15698/cst2023.03.277","url":null,"abstract":"<p><p>Recent observations indicate that the pathogenesis and prognosis of hormone-receptor breast cancer is not only dictated by the properties of the malignant cells but also by immune and microbial parameters. Thus, the immunosurveillance system retards the development of hormone-positive breast cancer and contributes to the therapeutic efficacy of estrogen receptor antagonists and aromatase inhibitors. Moreover, the anticancer immune response is profoundly modulated by the local and intestinal microbiota, which influences cancer cell-intrinsic signaling pathways, affects the composition and function of the immune infiltrate present in the tumor microenvironment and modulates the metabolism of estrogens. Indeed, specific bacteria in the gut produce enzymes that affect the enterohepatic cycle of estrogen metabolites, convert estrogens into androgens or generate estrogen-like molecules. The knowledge of these circuitries is in its infancy, calling for further in-depth analyses.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10012050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9138152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell StressPub Date : 2023-02-01DOI: 10.15698/cst2023.02.276
Shing Fai Chan, Keyur Vora, Rohan Dharmakumar
{"title":"Chronic heart failure following hemorrhagic myocardial infarction: mechanism, treatment and outlook.","authors":"Shing Fai Chan, Keyur Vora, Rohan Dharmakumar","doi":"10.15698/cst2023.02.276","DOIUrl":"https://doi.org/10.15698/cst2023.02.276","url":null,"abstract":"<p><p>Myocardial infarction (MI), the blockage of arterial blood supply of the heart, is among the most common causes of death worldwide. Even when patients receive immediate treatment by re-opening blocked arteries, they often develop chronic heart failure (CHF) in the aftermath of MI events. Yet, the factors that contribute to the development of MI-associated CHF are poorly understood. In our recent study (Nat Commun 13:6394), we link intramyocardial hemorrhage, an injury which can occur during reperfusion of areas affected by MI, to an increased risk of CHF. Mechanistically, our data suggest that an iron-induced adverse cascade of events after hemorrhagic MI drives fatty degeneration of infarcted tissue, which ultimately contributes to negative cardiac remodeling. In this Microreview, we discuss the implications of our findings regarding the molecular mechanism, more targeted treatment options as well as perspectives in the clinical care of CHF after hemorrhagic MI.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10102802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9310130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell StressPub Date : 2023-01-01DOI: 10.15698/cst2023.01.275
Maria Castedo, Antoine Lafarge, Guido Kroemer
{"title":"Poly(ADP-ribose) polymerase-1 and its ambiguous role in cellular life and death.","authors":"Maria Castedo, Antoine Lafarge, Guido Kroemer","doi":"10.15698/cst2023.01.275","DOIUrl":"https://doi.org/10.15698/cst2023.01.275","url":null,"abstract":"<p><p>The deletion of the gene coding for poly(ADP-ribose) polymerase-1 (PARP1) or its pharmacological inhibition protects mice against cerebral ischemia and Parkinson's disease. In sharp contrast, PARP1 inhibitors are in clinical use for the eradication of vulnerable cancer cells. It appears that excessive PARP1 activation is involved in a specific cell death pathway called parthanatos, while inhibition of PARP1 in cancer cells amplifies DNA damage to a lethal level. Hence, PARP1 plays a context-dependent role in cell fate decisions. In addition, it appears that PARP1 plays an ambiguous role in organismal aging.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9877585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10667744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell StressPub Date : 2022-12-01DOI: 10.15698/cst2022.12.274
Niki Ktena, Stefanos Ioannis Kaplanis, Irina Kolotuev, Alexandros Georgilis, Emmanouela Kallergi, Vasiliki Stavroulaki, Vassiliki Nikoletopoulou, Maria Savvaki, Domna Karagogeos
{"title":"Autophagic degradation of CNS myelin maintains axon integrity.","authors":"Niki Ktena, Stefanos Ioannis Kaplanis, Irina Kolotuev, Alexandros Georgilis, Emmanouela Kallergi, Vasiliki Stavroulaki, Vassiliki Nikoletopoulou, Maria Savvaki, Domna Karagogeos","doi":"10.15698/cst2022.12.274","DOIUrl":"https://doi.org/10.15698/cst2022.12.274","url":null,"abstract":"<p><p>(Macro)autophagy is a major lysosome-dependent degradation mechanism which engulfs, removes and recycles unwanted cytoplasmic material, including damaged organelles and toxic protein aggregates. Although a few studies implicate autophagy in CNS demyelinating pathologies, its role, particularly in mature oligodendrocytes and CNS myelin, remains poorly studied. Here, using both pharmacological and genetic inhibition of the autophagic machinery, we provide evidence that autophagy is an essential mechanism for oligodendrocyte maturation <i>in vitro</i>. Our study reveals that two core myelin proteins, namely proteolipid protein (PLP) and myelin basic protein (MBP) are incorporated into autophagosomes in oligodendrocytes, resulting in their degradation. Furthermore, we ablated <i>atg5</i>, a core gene of the autophagic machinery, specifically in myelinating glial cells <i>in vivo</i> by tamoxifen administration (<i>plp-Cre</i> <sup><i>ERT2</i></sup> <i>; atg5</i> <sup><i>f/f</i></sup> ) and showed that myelin maintenance is perturbed, leading to PLP accumulation. Significant morphological defects in myelin membrane such as decompaction accompanied with increased axonal degeneration are observed. As a result, the mice exhibit behavioral deficits. In summary, our data highlight that the maintenance of adult myelin homeostasis in the CNS requires the involvement of a fully functional autophagic machinery.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9707329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10740631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell StressPub Date : 2022-11-01DOI: 10.15698/cst2022.11.273
Bonell Patiño-Escobar, Ian D Ferguson, Arun P Wiita
{"title":"Unraveling the surface proteomic profile of multiple myeloma to reveal new immunotherapeutic targets and markers of drug resistance.","authors":"Bonell Patiño-Escobar, Ian D Ferguson, Arun P Wiita","doi":"10.15698/cst2022.11.273","DOIUrl":"https://doi.org/10.15698/cst2022.11.273","url":null,"abstract":"<p><p>The cell surface proteome (\"surfaceome\") serves as the interface between diseased cells and their local microenvironment. In cancer, this compartment is critical not only for defining tumor biology but also serves as a rich source of potential therapeutic targets and diagnostic markers. Recently, we profiled the surfaceome of the blood cancer multiple myeloma, an incurable plasma cell malignancy. While available small molecule agents can drive initial remissions in myeloma, resistance inevitably occurs. Several new classes of immunotherapies targeting myeloma surface antigens, including antibody therapeutics and chimeric antigen receptor (CAR) T-cells, can further prolong survival. However, new approaches are still needed for those who relapse. We thus applied the glycoprotein cell surface capture (CSC) methodology to panel of multiple myeloma cell lines, identifying key surface protein features of malignant plasma cells. We characterized the most abundant surface proteins on plasma cells, nominating CD48 as a high-density antigen favorable for a possible avidity-based strategy to enhance CAR-T efficacy. After chronic resistance to proteasome inhibitors, a first-line therapy, we found significant alterations in the surface profile of myeloma cells, including down-regulation of CD50, CD361/EVI2B, and CD53, while resistance to another first-line therapy, lenalidomide, drove increases in CD33 and CD45/PTPRC. In contrast, short-term treatment with lenalidomide led to upregulation of the surface antigen MUC-1, thereby enhancing efficacy of MUC-1 targeting CAR-T cells. Integrating our proteomics data with available transcriptome datasets, we developed a scoring system to rank potential standalone immunotherapy targets. Novel targets of interest included CCR10, TXNDC11, and LILRB4. We developed proof-of-principle CAR-T cells versus CCR10 using its natural ligand, CCL27, as an antigen recognition domain. Finally, we developed a \"miniaturized\" version of the CSC methodology and applied it to primary myeloma patient specimens. Overall, our work creates a unique resource for the myeloma community. This study also supports unbiased surface proteomic profiling as a fruitful strategy for identifying new therapeutic targets and markers of drug resistance, that could have utility in improving myeloma patient outcomes. Similar approaches could be readily applied to additional tumor types or even models/tissues derived from other diseases.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9984593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pyroptosis in NLRP3 inflammasome-related atherosclerosis.","authors":"Xiang Zeng, Dongling Liu, Xia Huo, Yue Wu, Cuiqing Liu, Qinghua Sun","doi":"10.15698/cst2022.10.272","DOIUrl":"https://doi.org/10.15698/cst2022.10.272","url":null,"abstract":"<p><p>Pyroptosis is a proinflammatory form of programmed cell death in response to inflammation. It involves in the pathogenesis and outcomes of atherosclerosis characterized by NLRP3 inflammasome assembly, membrane pore formation, cell swelling, pro-inflammatory mediator and cytokine release. There are known pyroptosis molecular pathways including the caspase-1 depended canonical signaling pathway and the caspase-4/5/11 determined non-canonical signaling pathway. It is essential to explore the connection among NLRP3 inflammasome, pyroptosis and atherosclerosis, which may shed light on the potential therapeutic strategies that target pyroptosis in atherosclerotic treatment.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2022-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9549904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40434331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}