Abstract 4072: Insulin and NADPH-generating enzymes as molecular targets to repress colon cancer cell proliferation

Abstract

Abstract An increasing body of evidence implicates obesity and the attendant hyperinsulinemia as major risk factors for human colorectal cancers. The lipogenic pathway supports growth and survival of colon cancer cells. In particular, inhibition of Fatty Acid Synthase (FASN) or Acetyl-CoA Carboxylase α (ACCα) induces apoptosis of colon cancer cells. The relative involvement in colon cancer initiation, progression and pathogenesis of cytosolic NADPH that is used in lipogenesis remains less clear. In the present study, we have determined the effects of insulin and the involvement of the major NADPH-generating cytosolic enzymes on proliferation of human colon cancer cell lines. Insulin (1-10 nM; to mimic normo- to hyper-insulinemic states) induced a significant increase (7-15%, p < 0.05) in proliferation of HT-29 and HCT-116 colon cancer cell lines in vitro (assayed by MTT assay). Addition of insulin augmented (by 5-10%) proliferation of both cell lines upon concurrent treatment with cancer chemotherapeutic agents (5-fluorouracil, oxaliplatin, irinotecan; each added at a dose < EC50). The insulin-mediated increase in HT-29 cell growth was associated with a 2-3 fold elevation in FASN gene expression and a 50% decrease in expression of the FASN-targeting micro RNAs, miR-103 and miR-107. However, insulin did not induce mRNA abundance for the cytoplasmic NADPH-generating enzymes [Malic Enzyme 1 (ME1), Glucose 6-Phosphate Dehydrogenase (G6PD), 6-Phosphogluconate Dehydrogenase (6PGD), or Isocitrate Dehydrogenase-1 (IDH1]. siRNA-mediated knockdown of FASN or of the individual major cytosolic NADPH-generating enzymes caused decreases in proliferation of HT-29 and HCT-116 cells (15-30%, p < 0.05) compared to the control scrambled siRNA. Data highlight pro-proliferative roles for insulin, FASN and cytosolic NADPH-generating enzymes in colorectal cancer cell growth. Implementation of pharmacologic and/or nutritional means to reduce serum insulin levels, enhance FASN miR expression and inhibit tumor cell NADPH-generation may serve as useful adjuncts for future cancer treatment and prevention. Supported by NIH grant RO1 CA136493 and the Arkansas Biosciences Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4072. doi:10.1158/1538-7445.AM2011-4072