Please use this identifier to cite or link to this item:
|Title:||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|
|Authors:||Lui, VWY;Tsao, SW;Lau, CPY;Cheung, CSF;Ho, K;Ng, MHL;Cheng, SH;Hong, B;Tsang, CM;Lei, KIK;Yamasaki, Y;Mita, A;Chan, ATC|
|Publisher:||Elsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/biochempharm|
|Description:||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 (IC 50:∼13-44nM). Moreover, cisplatin-resistant NPC cells were highly sensitive to ECyd (at nM concentration). The ECyd-mediated growth inhibition was associated with G 2/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. © 2010 Elsevier Inc.|
|Standard no:||Biochemical Pharmacology, 2010, v. 79 n. 12, p. 1772-1780|
|Appears in Collections:||Department of Anatomy|
Files in This Item:
Click on the URI links for accessing contents.
Items in HannanDL are protected by copyright, with all rights reserved, unless otherwise indicated.