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

Katie L. Bailey, Ekta Agarwal, Sanjib Chowdhury, Jiangtao Luo, Michael G. Brattain, Jennifer D. Black, Jing Wang

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere0176096
JournalPloS one
Volume12
Issue number4
DOIs
StatePublished - Apr 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Bailey, K. L., Agarwal, E., Chowdhury, S., Luo, J., Brattain, M. G., Black, J. D., & Wang, J. (2017). TGFβ/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells. PloS one, 12(4), [e0176096]. https://doi.org/10.1371/journal.pone.0176096