{"title":"Clitocine enhances the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis.","authors":"Feng Ruan, Yanyun Ruan, Huamin Gu, Jianguo Sun, Qi Chen","doi":"10.1152/ajpcell.00310.2024","DOIUrl":"10.1152/ajpcell.00310.2024","url":null,"abstract":"<p><p>Chemotherapy resistance to colon cancer is an unavoidable obstacle in the clinical management of the disease. Clitocine, an adenosine analog, played a significant role in the chemosensitivity of human colon cancer cells by promoting myeloid cell leukemia 1 (MCL-1) protein degradation. However, the detailed mechanism remains to be further elucidated. We found that clitocine upregulates the expression of F-box and WD repeat domain containing 7 (FBXW7), a ubiquitin ligase involved in the MCL-1 degradation. Transcriptome sequencing analysis revealed that clitocine significantly inhibits the cyclic adenosine monophosphate (cAMP) and extracellular regulated protein kinases (ERK) downstream signaling pathways in colon cancer cells, thereby enhancing FBXW7 expression and subsequently promoting the ubiquitination degradation of MCL-1 protein. We verified that clitocine regulated intracellular cAMP levels by competitive binding with the adenosine receptor A2B. A molecular docking assay also verified the binding relationship. By decreasing intracellular cAMP levels, clitocine blocks the activation of downstream signaling pathways, which ultimately enhances the drug sensitivity of colon cancer cells through increased FBXW7 expression due to the inhibition of its promoter DNA methylation. Both knockout of the adenosine receptor A2B and Br-cAMP treatment can effectively attenuate the function of clitocine in vitro and in vivo. This study clarified that clitocine enhanced the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis, providing further knowledge of the clinical application for clitocine.<b>NEW & NOTEWORTHY</b> Our study found that clitocine enhances the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C884-C900"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974842","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}
Kristen L Segars, Nicholas Azzari, Malia Cole, Landon Kushimi, Srikar Rapaka, Celeste B Rich, Vickery Trinkaus-Randall
{"title":"Diverse calcium signaling profiles regulate migratory behavior in avascular wound healing and aberrant signal hierarchy occurs early in diabetes.","authors":"Kristen L Segars, Nicholas Azzari, Malia Cole, Landon Kushimi, Srikar Rapaka, Celeste B Rich, Vickery Trinkaus-Randall","doi":"10.1152/ajpcell.00249.2024","DOIUrl":"10.1152/ajpcell.00249.2024","url":null,"abstract":"<p><p>In avascular wound repair, calcium signaling events are the predominant mechanism cells use to transduce information about stressors in the environment into an effective and coordinated migratory response. Live cell imaging and computational analysis of corneal epithelial wound healing revealed that signal initiation and propagation at the wound edge are highly ordered, with groups of cells engaging in cyclical patterns of initiation and propagation. The cells in these groups exhibit a diverse range of signaling behavior, and dominant \"conductor cells\" drive activity in groups of lower-signaling neighbors. Ex vivo model systems reveal that conductor cells are present in wing cell layers of the corneal epithelium and that signaling propagates both within and between wing and basal layers. There are significant aberrations in conductor phenotype and interlayer propagation in type II diabetic murine models, indicating that signal hierarchy breakdown is an early indicator of disease. In vitro models reveal that signaling profile diversity and conductor cell phenotype is eliminated with P2X7 inhibition and is altered in Pannexin-1 or P2Y2 but not Connexin-43 inhibition. Conductor cells express significantly less P2X7 than their lower-signaling neighbors and exhibit significantly less migratory behavior after injury. Together, our results show that the postinjury calcium signaling cascade exhibits significantly more ordered and hierarchical behavior than previously thought, that proteins previously shown to be essential for regulating motility are also essential for determining signaling phenotype, and that loss of signal hierarchy integrity is an early indicator of disease state. <b>NEW & NOTEWORTHY</b> Calcium signaling in corneal epithelial cells after injury is highly ordered, with groups of cells engaged in cyclical patterns of event initiation and propagation driven by high-signaling cells. Signaling behavior is determined by P2X7, Pannexin-1, and P2Y2 and influences migratory behavior. Signal hierarchy is observed in healthy ex vivo models after injury and becomes aberrant in diabetes. This represents a paradigm shift, as signaling was thought to be random and determined by factors in the environment.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1051-C1072"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915845","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}
{"title":"Hypomethylation-associated ELF3 helps nasopharyngeal carcinoma to escape immune surveillance via MUC16-mediated glycolytic metabolic reprogramming.","authors":"Yueyang Liu, Hong Zhou, Qi Yu, Qiang Wang","doi":"10.1152/ajpcell.00438.2024","DOIUrl":"10.1152/ajpcell.00438.2024","url":null,"abstract":"<p><p>Immune escape and metabolic reprogramming are two essential hallmarks of cancer. Mucin-16 (MUC16) has been linked to glycolysis and immune response in different cancers. However, its involvement in nasopharyngeal carcinoma (NPC) has not been well described. We seek to dissect the functions and detailed mechanisms of MUC16 in NPC. Bioinformatics prediction was performed to identify NPC-related molecules. MUC16 was significantly enhanced in NPC tissues, which was correlated with the advanced tumor stage of patients. Lentiviral plasmids-mediated MUC16 deletion inhibited the malignant behavior of NPC cells, and glycolysis inhibition by MUC16 deletion blocked immune escape in NPC cells. E74-like factor 3 (ELF3) bound to the MUC16 promoter promotes the transcription of MUC16. MUC16 overexpression reversed the repressive effect of ELF3 silencing on glycolysis and immune escape in NPC and accelerated tumor growth in vivo. Overexpression of ELF3 in NPC was associated with reduced DNA methylation in its promoter. Our findings revealed the role of the ELF3/MUC16 axis in the immune escape and metabolic reprogramming of NPC, providing potential therapeutic targets for NPC.<b>NEW & NOTEWORTHY</b> We identified the functions of E74-like factor 3 (ELF3) in glycolysis and immune escape of nasopharyngeal carcinoma cells for the first time. As a transcription factor, ELF3 promoted mucin-16 (MUC16) expression by binding to its promoter, leading to the glycolysis-mediated immune escape of nasopharyngeal carcinoma (NPC) cells. Targeting the ELF3/MUC16 axis generates a superior antitumor immune response, which will help establish a novel approach to restore protective antitumor immunity for NPC immunotherapy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1125-C1142"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103510","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}
{"title":"Modulating endothelial cell dynamics in fat grafting: the impact of DLL4 siRNA via adipose stem cell extracellular vesicles.","authors":"Sen-Lin Deng, Qiang Fu, Qing Liu, Fu-Jun Huang, Miao Zhang, Xun Zhou","doi":"10.1152/ajpcell.00186.2024","DOIUrl":"10.1152/ajpcell.00186.2024","url":null,"abstract":"<p><p>In the context of improving the efficacy of autologous fat grafts (AFGs) in reconstructive surgery, this study delineates the novel use of adipose-derived mesenchymal stem cells (ADSCs) and their extracellular vesicles (EVs) as vehicles for delivering delta-like ligand 4 (DLL4) siRNA. The aim was to inhibit DLL4, a gene identified through transcriptome analysis as a critical player in the vascular endothelial cells of AFG tissues, thereby negatively affecting endothelial cell functions and graft survival through the Notch signaling pathway. By engineering ADSC EVs to carry DLL4 siRNA (ADSC EVs-siDLL4), the research demonstrated a marked improvement in endothelial cell proliferation, migration, and lumen formation, and enhanced angiogenesis in vivo, leading to a significant increase in the survival rate of AFGs. This approach presents a significant advancement in the field of tissue engineering and regenerative medicine, offering a potential method to overcome the limitations of current fat grafting techniques.<b>NEW & NOTEWORTHY</b> This study introduces a groundbreaking method for enhancing autologous fat graft survival using adipose-derived stem cell extracellular vesicles (ADSC EVs) to deliver DLL4 siRNA. By targeting the delta-like ligand 4 (DLL4) gene, crucial in endothelial cell dynamics, this innovative approach significantly improves endothelial cell functions and angiogenesis, marking a substantial advancement in tissue engineering and regenerative medicine.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C929-C945"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888257","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}
Jichao Zhang, Zhao Yang, Congcong Zhang, Shijuan Gao, Yan Liu, Yingkai Li, Songyuan He, Jing Yao, Jie Du, Bin You, Yingchun Han
{"title":"PALMD haploinsufficiency aggravates extracellular matrix remodeling in vascular smooth muscle cells and promotes calcification.","authors":"Jichao Zhang, Zhao Yang, Congcong Zhang, Shijuan Gao, Yan Liu, Yingkai Li, Songyuan He, Jing Yao, Jie Du, Bin You, Yingchun Han","doi":"10.1152/ajpcell.00217.2024","DOIUrl":"10.1152/ajpcell.00217.2024","url":null,"abstract":"<p><p>Reduced PALMD expression is strongly associated with the development of calcified aortic valve stenosis; however, the role of PALMD in vascular calcification remains unknown. Calcified arteries were collected from mice to detect PALMD expression. Heterozygous <i>Palmd</i> knockout (<i>Palmd</i><sup>+/-</sup>) mice were established to explore the role of PALMD in subtotal nephrectomy-induced vascular calcification. RNA sequencing was applied to detect molecular changes in aortas from <i>Palmd</i><sup>+/-</sup> mice. Primary <i>Palmd</i><sup>+/-</sup> vascular smooth muscle cells (VSMCs) or PALMD-silenced VSMCs by short interfering RNA were used to analyze PALMD function in phenotypic changes and calcification. PALMD haploinsufficiency aggravated subtotal nephrectomy-induced vascular calcification. RNA sequencing analysis showed that loss of PALMD disturbed the synthesis and degradation of the extracellular matrix (ECM) in aortas, including collagens and matrix metalloproteinases (<i>Col6a6</i>, <i>Mmp2</i>, <i>Mmp9</i>, etc.). In vitro experiments revealed that PALMD-deficient VSMCs were more susceptible to high phosphate-induced calcification. Downregulation of SMAD6 expression and increased levels of p-SMAD2 were detected in <i>Palmd</i><sup>+/-</sup> VSMCs, suggesting that transforming growth factor-β signaling may be involved in PALMD haploinsufficiency-induced vascular calcification. Our data revealed that PALMD haploinsufficiency causes ECM dysregulation in VSMCs and aggravates vascular calcification. Our findings suggest that reduced PALMD expression is also linked to vascular calcification, and PALMD may be a potential therapeutic target for this disease. <b>NEW & NOTEWORTHY</b> We found that PALMD haploinsufficiency causes extracellular matrix dysregulation, reduced PALMD expression links to vascular calcification, and PALMD mutations may lead to the risk of both calcific aortic valve stenosis and vascular calcification.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1012-C1022"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153028","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}
Sarannya Edamana, Frédéric H. Login, Andreas Riishede, Vibeke S. Dam, Teresa Kirkegaard, Lene N. Nejsum
{"title":"The water channels Aquaporin-1 and Aquaporin-3 interact with and affect the cell polarity protein Scribble in 3D in vitro models of breast cancer","authors":"Sarannya Edamana, Frédéric H. Login, Andreas Riishede, Vibeke S. Dam, Teresa Kirkegaard, Lene N. Nejsum","doi":"10.1152/ajpcell.00094.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00094.2024","url":null,"abstract":"American Journal of Physiology-Cell Physiology, Ahead of Print. <br/>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"119 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266490","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}
Tomislav Smoljo, Hrvoje Lalic, Vilma Dembitz, Barbara Tomic, Josip Batinic, Radovan Vrhovac, Antonio Bedalov, Dora Visnjic
{"title":"Bone Marrow Stromal Cells Enhance Differentiation of Acute Myeloid Leukemia Induced by Pyrimidine Synthesis Inhibitors","authors":"Tomislav Smoljo, Hrvoje Lalic, Vilma Dembitz, Barbara Tomic, Josip Batinic, Radovan Vrhovac, Antonio Bedalov, Dora Visnjic","doi":"10.1152/ajpcell.00413.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00413.2024","url":null,"abstract":"American Journal of Physiology-Cell Physiology, Ahead of Print. <br/>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"99 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266489","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}
Ting Liu, Jialing Yuan, Caihong Dai, Mystie X Chen, Jerry Fan, Benjamin D. Humphreys, David J. Fulton, Daniel T. Kleven, Xingjun Fan, Zheng Dong, Jian-Kang Chen
{"title":"Pik3c3 Expression Profiling in the Mouse Kidney and Its Role in Proximal Tubule Cell Physiology","authors":"Ting Liu, Jialing Yuan, Caihong Dai, Mystie X Chen, Jerry Fan, Benjamin D. Humphreys, David J. Fulton, Daniel T. Kleven, Xingjun Fan, Zheng Dong, Jian-Kang Chen","doi":"10.1152/ajpcell.00564.2023","DOIUrl":"https://doi.org/10.1152/ajpcell.00564.2023","url":null,"abstract":"American Journal of Physiology-Cell Physiology, Ahead of Print. <br/>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"4 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142204166","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}