title: Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation.
abstract: 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 downregulation 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.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Qian
authors.forename: H-H
authors.initials: HH
authors.lastname: Ma
authors.forename: R
authors.initials: R
authors.lastname: Jin
authors.forename: P-X
authors.initials: PX
authors.lastname: Yang
authors.forename: M-Y
authors.initials: MY
authors.lastname: Cai
authors.forename: Y-H
authors.initials: YH
authors.lastname: Liu
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Liao
authors.forename: H-X
authors.initials: HX
authors.lastname: Deng
authors.forename: S-J
authors.initials: SJ
authors.lastname: Mai
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: Y-X
authors.initials: YX
authors.lastname: Zeng
authors.forename: M C
authors.initials: MC
authors.lastname: Lin
authors.forename: H-F
authors.initials: HF
authors.lastname: Kung
authors.forename: D
authors.initials: D
authors.lastname: Xie
authors.forename: J-J
authors.initials: JJ
authors.lastname: Huang
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D019098:Telomerase / Q000502:physiology*; D016615:Telomere / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018943:Anthracyclines; D018797:Cell Cycle Proteins; C440808:PINX1 protein, human; D025521:Tumor Suppressor Proteins; D019098:Telomerase; D046988:Proteasome Endopeptidase Complex