Aldose reductase inhibition suppresses colon cancer cell viability by modulating microRNA-21 mediated programmed cell death 4 (PDCD4) expression

Inhibition of polyol pathway enzyme aldose reductase (AR) has been shown to prevent colon cancer cells growth in culture and in nude mice xenografts. However, the role of AR in the mediation of growth factor-induced colon cancer cells growth is not well understood. In this study, we have investigated how AR inhibition prevents tumour growth via regulation of microRNA (miR)-21-mediated programmed cell death 4 (PDCD4) expression in colon cancer cells in in vitro and in vivo. Treatment of colon cancer cells (HT29, SW480 and Caco-2) with epidermal growth factor (EGF) caused increased expression of miR-21 and inhibition of AR prevented it. Further, AR inhibition also increased PDCD4, a putative target of miR-21 in human colon cancer cells. Inhibition of AR also prevented EGF-induced phosphorylation of PDCD4. Treatment of HT29 cells with AR inhibitor, fidarestat, prevented the EGF-induced phosphorylation of mammalian target of rapamycin (mTOR), regulatory associated protein of mTOR (Raptor), eukaryotic initiation factor 4E (eIF4E), p70 S6 kinase (S6K) and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and increased the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK). Similarly, in nude mice xenograft tissues, PDCD4 and 4E-BP1 levels were significantly higher in AR inhibitor-treated mice compared to controls. Collectively, these results indicate that AR inhibition prevents growth factor-induced colon cancer growth by down-regulating miR-21 expression and increasing PDCD4 levels through the reactive oxygen species (ROS)/AMPK/mTOR/AP1/ 4E-BP1 pathway.