An RNA-directed nucleoside anti-metabolite, 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd), elicits antitumor effect via TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) downregulation |
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Authors: | Vivian Wai Yan Lui Cecilia Pik Yuk Lau Crystal Sao Fong Cheung Margaret Heung Ling Ng Bo Hong Chi Man Tsang Yasundo Yamasaki Anthony T.C. Chan |
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Affiliation: | a Cancer Drug Testing Unit, State Key Laboratory in Oncology in Southern China, Sir Y.K. Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute for Health Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China b Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China c Department of Anatomy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China d Taiho Pharmaceutical Co., Ltd., Tokyo, Japan |
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Abstract: | 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd) is a ribose-modified nucleoside analog of cytidine with potent anticancer activity in several cancers. The main antitumor mechanism of this promising RNA-directed nucleoside anti-metabolite is efficient blockade of RNA synthesis in cancer cells. Here, we examined the therapeutic potential of this RNA-directed anti-metabolite in in vitro models of nasopharyngeal cancer (NPC). In a panel of 6 NPC cell lines, ECyd effectively inhibited cellular proliferation at nM concentrations (IC50:∼13-44 nM). Moreover, cisplatin-resistant NPC cells were highly sensitive to ECyd (at nM concentration). The ECyd-mediated growth inhibition was associated with G2/M cell cycle arrest, PARP cleavage (a hallmark of apoptosis) and Bcl-2 downregulation, indicating induction of apoptosis by ECyd in NPC cells. Unexpectedly, ECyd-induced significant downregulation of TIGAR, a newly described dual regulator of apoptosis and glycolysis. More importantly, this novel action of ECyd on TIGAR was accompanied by marked depletion of NADPH, the major reducing power critically required for cell proliferation and survival. We hypothesized that ECyd-induced TIGAR downregulation was crucially involved in the antitumor activity of ECyd. Indeed, overexpression of TIGAR was able to rescue NPC cells from ECyd-induced growth inhibition, demonstrating a novel mechanistic action of ECyd on TIGAR. We demonstrated for the first time that an RNA-directed nucleoside analog, ECyd, exerts its antitumor activity via downregulation of a novel regulator of apoptosis, TIGAR. Moreover, ECyd may represent a novel therapy for NPC. |
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Keywords: | ECyd, 1-(3-C-ethynyl-beta- smallcaps" >d-ribo-pentofuranosyl)cytosine NPC, nasopharyngeal carcinoma LMP1, latent membrane protein 1 TIGAR, TP53-induced glycolysis and apoptosis regulator DRB, 5,6-dichloro-1-β- smallcaps" >d-ribofuranosylbenzimidazole ARC, 4-amino-6-hydrazino-7-beta- smallcaps" >d-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide EUrd, 1-(3-C-ethynyl-beta- smallcaps" >d-ribopentofuranosyl)uracil |
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