Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation
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摘要Telomere maintenance is essential for cancer growth. Induction of telomere dysfunction, for example, by inhibition of telomeric proteins or telomerase, has been shown to strongly enhance cancer cells' sensitivity to chemotherapies. However, it is not clear whether modulations of telomere maintenance constitute cancer cellular responses to chemotherapies. Furthermore, the manner in which anti-cancer drugs affect telomere function remains unknown. In this study, we show that anthracyclines, a class of anti-cancer drugs widely used in clinical cancer treatments, have an active role in triggering telomere dysfunction specifically in telomerase-positive cancer cells. Anthracyclines interrupt telomere maintenance by telomerase through the down-regulation of PinX1, a protein factor responsible for targeting telomerase onto telomeres, thereby inhibiting telomerase association with telomeres. We further demonstrate that anthracyclines downregulate PinX1 by inducing this protein degradation through the ubiquitin-proteasome-dependent pathway. Our data not only reveal a novel action for anthracyclines as telomerase functional inhibitors but also provide a clue for the development of novel anti-cancer drugs based on telomerase/telomere targeting, which is actively investigated by many current studies. Oncogene (2012) 31, 1-12; doi: 10.1038/onc.2011.214; published online 6 June 2011
著者Zhang B, Qian D, Ma HH, Jin R, Yang PX, Cai MY, Liu YH, Liao YJ, Deng HX, Mai SJ, Zhang H, Zeng YX, Lin MC, Kung HF, Xie D, Huang JJ
期刊名稱Oncogene
出版年份2012
月份1
日期1
卷號31
期次1
出版社NATURE PUBLISHING GROUP
頁次1 - 12
國際標準期刊號0950-9232
電子國際標準期刊號1476-5594
語言英式英語
關鍵詞anthracyclines; cancer; PinX1; telomerase; telomere dysfunction
Web of Science 學科類別Biochemistry & Molecular Biology; BIOCHEMISTRY & MOLECULAR BIOLOGY; Cell Biology; CELL BIOLOGY; Genetics & Heredity; GENETICS & HEREDITY; Oncology; ONCOLOGY

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