talk between the insulin and Wnt signaling pathways: evidence from intestinal endocrine L cells

Type II diabetes and hyperinsulinemia are associated with increased risks of developing colorectal cancer (CRC). Detailed mechanisms underlying this correlation, however, are yet to be explored. The present study demonstrates that insulin increases the expression of proto-oncogenes c-Myc and cyclin D1 via both translational and transcriptional mechanisms. We show here that insulin stimulates c-Myc gene translation via an Akt/PKB-dependent mechanism involving the mTOR signaling pathway. More importantly, we show for the first time that transcriptional stimulation of c-Myc and cyclin D1 expression by insulin involves a novel Akt/PKB-independent signal crosstalk between insulin and canonical Wnt signaling pathways. We then identified p21-activated protein kianse 1 (PAK-1) as a novel mediator for insulin and Wnt/beta-catenin (-cat) molecular crosstalk, involving MEK/ERK signaling. Furthermore, we found that insulin treatment leads to increased -cat phosphorylation at Ser675, and this is associated with increased -cat nuclear content and increased -cat interaction with Tcf/Lef-binding elements (TBEs) of th