Gemcitabine causes telomere attrition by stabilizing TRF2.
Gemcitabine is an effective anti-cancer agent against solid tumors. The pharmacological mechanism of gemcitabine is known as incorporation into DNA and thereby inhibition of DNA synthesis. When used in metronomic chemotherapy of cancer, the agent may inhibit angiogenesis. It is still uncertain whether the agent can inhibit tumor growth by a mechanism other than DNA incorporation. In this report, we show that gemcitabine causes telomere shortening by stabilizing TRF2 that is required for XPF-dependent telomere loss. Overexpression of TRF2 in the absence of gemcitabine also causes telomere shortening with simultaneous association of TRF2 with XPF/ERCC1. Our study provides a new mechanism by which gemcitabine exerts its anti-tumor activity.
Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155 Sec 2 Linong St., Taipei, Taiwan.
Chih-Hao
CH
Su
Wei-Chih
WC
Chu
Keng-Hsin
KH
Lan
Chung-Pin
CP
Li
Yee
Y
Chao
Han-Chieh
HC
Lin
Shou-Dong
SD
Lee
Ying-Chieh
YC
Tsai
Wei-Ping
WP
Lee
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004720:Endonucleases / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006207:Half-Life; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009363:Neoplasm Proteins / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012150:Polymorphism, Restriction Fragment Length; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D016615:Telomere / Q000187:drug effects* / Q000648:ultrastructure; D035341:Telomeric Repeat Binding Protein 2 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; C095888:xeroderma pigmentosum group F protein; D003841:Deoxycytidine; C071447:ERCC1 protein, human; D004720:Endonucleases; D000093542:Gemcitabine