In this study, we have uncovered a novel crosstalk between TGFβ 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 TGFβ/Smad3 signaling. Loss or attenuation of TGFβ 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 TGFβ/Smad3 signaling inhibits cell proliferation and increases apoptosis at least partially through the inhibition of IRS-1 expression and activation. Additionally, the TGFβ/Smad3/IRS-1 signaling axis regulates expression of cyclin D1 and XIAP, which may contribute to TGFβ/Smad3/IRS-1-mediated cell cycle progression and survival. Given that loss of TGFβ 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.
Adaptor Proteins, Signal Transducing, Apoptosis, Cell Line, Tumor, Cell Proliferation, Colon, Colonic Neoplasms, Cyclin D1, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Insulin Receptor Substrate Proteins, Phosphorylation, Signal Transduction, Smad3 Protein, Transforming Growth Factor beta, X-Linked Inhibitor of Apoptosis Protein
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Bailey, Katie L.; Agarwal, Ekta; Chowdhury, Sanjib; Luo, Jiangtao; Brattain, Michael G.; Black, Jennifer D.; and Wang, J., "TGFβ/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells." (2017). Journal Articles: Eppley Institute. 25.