Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert B Ozturk, Thamil S Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung H Shin, Kerem Fidan, Joo-Leng Low, Joelle Y H Chua, Yap C Kong, Ong Y Qi, Emile Tan, Aik Y Chok, Isaac Seow-En, Ian Wee, Dominique C Macalinao, Dawn Q Chong, Hong Y Chang, Fiona Lee, Wei Q Leow, Maki Murata-Hori, Zhang Xiaoqian, Chia Shumei, Chris S H Tan, Ramanuj Dasgupta, Iain B Tan, Vinay Tergaonkar
{"title":"铁(Fe3+)依赖性端粒酶再激活驱动结直肠癌。","authors":"Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert B Ozturk, Thamil S Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung H Shin, Kerem Fidan, Joo-Leng Low, Joelle Y H Chua, Yap C Kong, Ong Y Qi, Emile Tan, Aik Y Chok, Isaac Seow-En, Ian Wee, Dominique C Macalinao, Dawn Q Chong, Hong Y Chang, Fiona Lee, Wei Q Leow, Maki Murata-Hori, Zhang Xiaoqian, Chia Shumei, Chris S H Tan, Ramanuj Dasgupta, Iain B Tan, Vinay Tergaonkar","doi":"10.1158/2159-8290.CD-23-1379","DOIUrl":null,"url":null,"abstract":"<p><p>Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with an increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by reactivating the dormant human telomerase reverse transcriptase (hTERT) subunit of the telomerase holoenzyme in an iron-(Fe3+)-dependent manner and thereby drives colorectal cancers. Chemical genetic screens combined with isothermal dose-response fingerprinting and mass spectrometry identified a small molecule SP2509 that specifically inhibits Pirin-mediated hTERT reactivation in colorectal cancers by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat and increased incidence of colorectal cancers. Small molecules like SP2509 represent a novel modality to target telomerase that acts as a driver of 90% of human cancers and is yet to be targeted in clinic. Significance: We show how iron-(Fe3+) in collusion with genetic factors reactivates telomerase, providing a molecular mechanism for the association between iron overload and increased incidence of colorectal cancers. Although no enzymatic inhibitors of telomerase have entered the clinic, we identify SP2509, a small molecule that targets telomerase reactivation and function in colorectal cancers.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7000,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450372/pdf/","citationCount":"0","resultStr":"{\"title\":\"Iron-(Fe3+)-Dependent Reactivation of Telomerase Drives Colorectal Cancers.\",\"authors\":\"Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert B Ozturk, Thamil S Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung H Shin, Kerem Fidan, Joo-Leng Low, Joelle Y H Chua, Yap C Kong, Ong Y Qi, Emile Tan, Aik Y Chok, Isaac Seow-En, Ian Wee, Dominique C Macalinao, Dawn Q Chong, Hong Y Chang, Fiona Lee, Wei Q Leow, Maki Murata-Hori, Zhang Xiaoqian, Chia Shumei, Chris S H Tan, Ramanuj Dasgupta, Iain B Tan, Vinay Tergaonkar\",\"doi\":\"10.1158/2159-8290.CD-23-1379\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with an increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by reactivating the dormant human telomerase reverse transcriptase (hTERT) subunit of the telomerase holoenzyme in an iron-(Fe3+)-dependent manner and thereby drives colorectal cancers. Chemical genetic screens combined with isothermal dose-response fingerprinting and mass spectrometry identified a small molecule SP2509 that specifically inhibits Pirin-mediated hTERT reactivation in colorectal cancers by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat and increased incidence of colorectal cancers. Small molecules like SP2509 represent a novel modality to target telomerase that acts as a driver of 90% of human cancers and is yet to be targeted in clinic. 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Iron-(Fe3+)-Dependent Reactivation of Telomerase Drives Colorectal Cancers.
Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with an increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by reactivating the dormant human telomerase reverse transcriptase (hTERT) subunit of the telomerase holoenzyme in an iron-(Fe3+)-dependent manner and thereby drives colorectal cancers. Chemical genetic screens combined with isothermal dose-response fingerprinting and mass spectrometry identified a small molecule SP2509 that specifically inhibits Pirin-mediated hTERT reactivation in colorectal cancers by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat and increased incidence of colorectal cancers. Small molecules like SP2509 represent a novel modality to target telomerase that acts as a driver of 90% of human cancers and is yet to be targeted in clinic. Significance: We show how iron-(Fe3+) in collusion with genetic factors reactivates telomerase, providing a molecular mechanism for the association between iron overload and increased incidence of colorectal cancers. Although no enzymatic inhibitors of telomerase have entered the clinic, we identify SP2509, a small molecule that targets telomerase reactivation and function in colorectal cancers.
期刊介绍:
Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.