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

Vivian Wai Yan Lui, Cecilia Pik Yuk Lau, Crystal Sao Fong Cheung, Kakiu Ho, Margaret Heung Ling Ng, Suk Hang Cheng, Bo Hong, Sai Wah Tsao, Chi Man Tsang, Kenny Ieng Kit Lei, Yasundo Yamasaki, Akira Mita, Anthony T.C. Chan

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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:∼13-44nM). 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.

Original languageEnglish (US)
Pages (from-to)1772-1780
Number of pages9
JournalBiochemical Pharmacology
Volume79
Issue number12
DOIs
StatePublished - Jun 2010
Externally publishedYes

Keywords

  • Antitumor mechanism
  • ECyd
  • NADPH
  • NPC
  • TIGAR

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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