TGFβ/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells

• Published in: PloS one Vol. 12; no. 4; p. e0176096
• Main Authors: Bailey, Katie L, Agarwal, Ekta, Chowdhury, Sanjib, Luo, Jiangtao, Brattain, Michael G, Black, Jennifer D, Wang, Jing
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.04.2017; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Apoptosis; Apoptosis - genetics; Biology and life sciences; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - genetics; Colon - metabolism; Colon - pathology; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Cyclin D1 - metabolism; Down-Regulation - genetics; Gene Expression Regulation, Neoplastic - genetics; Humans; Insulin Receptor Substrate Proteins - antagonists & inhibitors; Kinases; Medicine and Health Sciences; Oncogenes; Phosphorylation - genetics; Signal transduction; Signal Transduction - genetics; Smad3 Protein - metabolism; Transforming Growth Factor beta - metabolism; X-Linked Inhibitor of Apoptosis Protein - metabolism; United States > US; Nebraska
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0176096

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.