Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells

I. Lu Lai, Chih Chien Chou, Po Ting Lai, Chun Sheng Fang, Lawrence A.Shirley, Ribai Yan, Xiaokui Mo, Mark Bloomston, Samuel K. Kulp, Tanios Bekaii-Saab, Ching Shih Chen

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Gemcitabine resistance remains a significant clinical challenge. Here, we used a novel glucose transporter (Glut) inhibitor, CG-5, as a proof-of-concept compound to investigate the therapeutic utility of targeting the Warburg effect to overcome gemcitabine resistance in pancreatic cancer. The effects of gemcitabine and/or CG-5 on viability, survival, glucose uptake and DNA damage were evaluated in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cell lines. Mechanistic studies were conducted to determine the molecular basis of gemcitabine resistance and the mechanism of CG-5-induced sensitization to gemcitabine. The effects of CG-5 on gemcitabine sensitivity were investigated in a xenograft tumor model of gemcitabine-resistant pancreatic cancer. In contrast to gemcitabine-sensitive pancreatic cancer cells, the resistant Panc-1 and Panc-1GemR cells responded to gemcitabine by increasing the expression of ribonucleotide reductase M2 catalytic subunit (RRM2) through E2F1-mediated transcriptional activation. Acting as a pan-Glut inhibitor, CG-5 abrogated this gemcitabineinduced upregulation of RRM2 through decreased E2F1 expression, thereby enhancing gemcitabine-induced DNA damage and inhibition of cell survival. This CG-5-induced inhibition of E2F1 expression was mediated by the induction of a previously unreported E2F1-targeted microRNA, miR-520f. The addition of oral CG-5 to gemcitabine therapy caused greater suppression of Panc- 1GemR xenograft tumor growth in vivo than either drug alone. Glut inhibition may be an effective strategy to enhance gemcitabine activity for the treatment of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)2203-2213
Number of pages11
JournalCarcinogenesis
Volume35
Issue number10
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Cancer Research

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    Lai, I. L., Chou, C. C., Lai, P. T., Fang, C. S., A.Shirley, L., Yan, R., Mo, X., Bloomston, M., Kulp, S. K., Bekaii-Saab, T., & Chen, C. S. (2014). Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells. Carcinogenesis, 35(10), 2203-2213. https://doi.org/10.1093/carcin/bgu124