Jinlong Cao , Siyu Chen , Jirong Wang , Xinpeng Fan , Shanhui Liu , Xiaoran Li , Li Yang
{"title":"转录因子PRRX1激活的ANXA6可促进表皮生长因子受体-PKCα复合物的形成，并增强膀胱癌对顺铂的敏感性。","authors":"Jinlong Cao , Siyu Chen , Jirong Wang , Xinpeng Fan , Shanhui Liu , Xiaoran Li , Li Yang","doi":"10.1016/j.lfs.2024.123228","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Tumor resistance to cisplatin represents a major clinical challenge, particularly in bladder cancer (BC). ANXA6 is a member of annexin family, and its role in cisplatin resistance remains unclear. This study explores ANXA6's role in promoting cisplatin sensitivity.</div></div><div><h3>Methods</h3><div>Bioinformatics analyses and clinical specimen verifications assessed the correlation between ANXA6 and cisplatin treatment. A series of assays, including CCK-8, clone formation assay, flow cytometry assays for reactive oxygen species (ROS) and apoptosis, and comet assays, were used to confirm ANXA6's role in enhancing cisplatin sensitivity and re-sensitizing resistant BC cells. Mass spectrometry, immunofluorescence, and co-immunoprecipitation experiments elucidated ANXA6's role in enhancing PKCα/EGFR complex formation and inhibiting the EGFR pathway. ChIP-PCR and dual-luciferase assays determined PRRX1's regulatory role on ANXA6 transcription. Finally, the impact of ANXA6 in vivo was evaluated using xenograft models.</div></div><div><h3>Results</h3><div>Bioinformatics analyses showed a significant correlation between ANXA6 expression and cisplatin sensitivity. In vitro and in vivo experiments confirmed that ANXA6 was a new target for cisplatin treatment. ANXA6 overexpression not only enhanced cell viability inhibition, DNA damage and apoptosis caused by cisplatin, but also re-sensitized cisplatin-resistant cells. Mechanistically, ANXA6 promotes PKCα/EGFR complex formation, inhibiting EGFR phosphorylation and downstream AKT and ERK1/2. Moreover, PRRX1 was identified as a transcription factor promoting ANXA6 expression, thereby augmenting the cytotoxic effects of cisplatin.</div></div><div><h3>Conclusion</h3><div>Our study reveals the mechanism by which ANXA6 enhances cisplatin sensitivity and re-sensitizes resistant cells. The roles of PRRX1 and ANXA6 in cisplatin resistance offer new therapeutic targets to overcome cisplatin resistance in clinical practice.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"359 ","pages":"Article 123228"},"PeriodicalIF":5.2000,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Transcription factor PRRX1-activated ANXA6 facilitates EGFR-PKCα complex formation and enhances cisplatin sensitivity in bladder cancer\",\"authors\":\"Jinlong Cao , Siyu Chen , Jirong Wang , Xinpeng Fan , Shanhui Liu , Xiaoran Li , Li Yang\",\"doi\":\"10.1016/j.lfs.2024.123228\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Tumor resistance to cisplatin represents a major clinical challenge, particularly in bladder cancer (BC). ANXA6 is a member of annexin family, and its role in cisplatin resistance remains unclear. This study explores ANXA6's role in promoting cisplatin sensitivity.</div></div><div><h3>Methods</h3><div>Bioinformatics analyses and clinical specimen verifications assessed the correlation between ANXA6 and cisplatin treatment. A series of assays, including CCK-8, clone formation assay, flow cytometry assays for reactive oxygen species (ROS) and apoptosis, and comet assays, were used to confirm ANXA6's role in enhancing cisplatin sensitivity and re-sensitizing resistant BC cells. Mass spectrometry, immunofluorescence, and co-immunoprecipitation experiments elucidated ANXA6's role in enhancing PKCα/EGFR complex formation and inhibiting the EGFR pathway. ChIP-PCR and dual-luciferase assays determined PRRX1's regulatory role on ANXA6 transcription. Finally, the impact of ANXA6 in vivo was evaluated using xenograft models.</div></div><div><h3>Results</h3><div>Bioinformatics analyses showed a significant correlation between ANXA6 expression and cisplatin sensitivity. In vitro and in vivo experiments confirmed that ANXA6 was a new target for cisplatin treatment. ANXA6 overexpression not only enhanced cell viability inhibition, DNA damage and apoptosis caused by cisplatin, but also re-sensitized cisplatin-resistant cells. Mechanistically, ANXA6 promotes PKCα/EGFR complex formation, inhibiting EGFR phosphorylation and downstream AKT and ERK1/2. Moreover, PRRX1 was identified as a transcription factor promoting ANXA6 expression, thereby augmenting the cytotoxic effects of cisplatin.</div></div><div><h3>Conclusion</h3><div>Our study reveals the mechanism by which ANXA6 enhances cisplatin sensitivity and re-sensitizes resistant cells. The roles of PRRX1 and ANXA6 in cisplatin resistance offer new therapeutic targets to overcome cisplatin resistance in clinical practice.</div></div>\",\"PeriodicalId\":18122,\"journal\":{\"name\":\"Life sciences\",\"volume\":\"359 \",\"pages\":\"Article 123228\"},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2024-11-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Life sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S002432052400818X\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S002432052400818X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Transcription factor PRRX1-activated ANXA6 facilitates EGFR-PKCα complex formation and enhances cisplatin sensitivity in bladder cancer
Background
Tumor resistance to cisplatin represents a major clinical challenge, particularly in bladder cancer (BC). ANXA6 is a member of annexin family, and its role in cisplatin resistance remains unclear. This study explores ANXA6's role in promoting cisplatin sensitivity.
Methods
Bioinformatics analyses and clinical specimen verifications assessed the correlation between ANXA6 and cisplatin treatment. A series of assays, including CCK-8, clone formation assay, flow cytometry assays for reactive oxygen species (ROS) and apoptosis, and comet assays, were used to confirm ANXA6's role in enhancing cisplatin sensitivity and re-sensitizing resistant BC cells. Mass spectrometry, immunofluorescence, and co-immunoprecipitation experiments elucidated ANXA6's role in enhancing PKCα/EGFR complex formation and inhibiting the EGFR pathway. ChIP-PCR and dual-luciferase assays determined PRRX1's regulatory role on ANXA6 transcription. Finally, the impact of ANXA6 in vivo was evaluated using xenograft models.
Results
Bioinformatics analyses showed a significant correlation between ANXA6 expression and cisplatin sensitivity. In vitro and in vivo experiments confirmed that ANXA6 was a new target for cisplatin treatment. ANXA6 overexpression not only enhanced cell viability inhibition, DNA damage and apoptosis caused by cisplatin, but also re-sensitized cisplatin-resistant cells. Mechanistically, ANXA6 promotes PKCα/EGFR complex formation, inhibiting EGFR phosphorylation and downstream AKT and ERK1/2. Moreover, PRRX1 was identified as a transcription factor promoting ANXA6 expression, thereby augmenting the cytotoxic effects of cisplatin.
Conclusion
Our study reveals the mechanism by which ANXA6 enhances cisplatin sensitivity and re-sensitizes resistant cells. The roles of PRRX1 and ANXA6 in cisplatin resistance offer new therapeutic targets to overcome cisplatin resistance in clinical practice.
期刊介绍：
Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed.
The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.
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