Abstract 2052: Inhibition of aldose reductase prevents hypoxic stress signaling in human colon cancer cells

Abstract

Abstract Hypoxia, a hallmark of invasive solid tumors and increased angiogenesis, is strongly associated with the progression of malignant phenotypes, poor prognosis, and resistance to chemo and radiation therapies. In a variety of cancers, hypoxic stress-induces inflammatory signaling which is mediated by specific cytokines, chemokines and growth factors. We have recently shown that inhibition of aldose reductase (AR), an enzyme that catalyzes the reduction of lipid aldehydes and their glutathione conjugates, prevents human colon cancer cell growth in culture as well as in nude mice xenografts by inhibiting the NF-kB-dependent activation of oxidative stress-mediated inflammatory and carcinogenic markers. However, the role of AR in mediating hypoxic stress signals is not known. We therefore investigated the molecular mechanisms by which AR inhibition prevents the hypoxia-induced human colon cancer cells growth and invasion. Our results indicate that AR inhibition by pharmacological inhibitor fidarestat or ablation by AR specific siRNA prevents hypoxia-induced proliferation of HT29 colon cancer cells. Further, hypoxia- induced increase in the level of HIF1a in HT29 cells was significantly decreased by AR inhibition. During hypoxic conditions treatment of HT29 cells with AR inhibitor, fidarestat significantly decreased the expression of VEGF, a down target of HIF1a, at both mRNA and protein levels and also prevented the activation of PI3K/AKT and GSK3b. Further, AR inhibition also prevented hypoxia-induced inflammatory molecules such as Cox-2 and PGE2 and expression of extracellular matrix proteins such as MMP2, vimentin, uPAR and LOX2. In addition, AR inhibition also prevented the hypoxia -induced tube formation (angiogenesis) in vascular endothelial cells. In conclusion, our results indicate that AR mediates hypoxia -induced tumor progression, invasion and angiogenesis which can be prevented by AR inhibition or ablation. 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 2052. doi:10.1158/1538-7445.AM2011-2052