TGF?/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells.

ABSTRACT: In this study, we have uncovered a novel crosstalk between TGF? and IGF-1R signaling pathways. We show for the first time that expression and activation of IRS-1, an IGF-1R adaptor protein, is decreased by TGF?/Smad3 signaling. Loss or attenuation of TGF? activation leads to elevated expression and phosphorylation of IRS-1 in colon cancer cells, resulting in enhanced cell proliferation, decreased apoptosis and increased tumor growth in vitro and in vivo. Downregulation of IRS-1 expression reversed Smad3 knockdown-mediated oncogenic phenotypes, indicating that TGF?/Smad3 signaling inhibits cell proliferation and increases apoptosis at least partially through the inhibition of IRS-1 expression and activation. Additionally, the TGF?/Smad3/IRS-1 signaling axis regulates expression of cyclin D1 and XIAP, which may contribute to TGF?/Smad3/IRS-1-mediated cell cycle progression and survival. Given that loss of TGF? signaling occurs frequently in colon cancer, an important implication of our study is that IRS-1 could be a potential therapeutic target for colon cancer treatment.

SUBMITTER: Bailey KL 

PROVIDER: S-EPMC5393866 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature