Dietary fiber enhances a tumor suppressor signaling pathway in the gut.

Abstract

To determine whether sodium butyrate (NaB), a major short-chain fatty acid produced in the human gut by bacterial fermentation of dietary fiber, enhances transforming growth factor (TGF)-beta signaling and potentiates its tumor suppressor activity in the gut. The molecular mechanisms by which dietary fiber decreases the risk of colon cancers are poorly characterized. TGF-beta is an important tumor suppressor in the gut and has many similar biologic activities as NaB. Therefore, we hypothesized that the chemo-preventive effects of NaB are mediated in part by enhancing TGF-beta signaling and its tumor suppressor function in the gut. The effects of NaB on Smad3 expression in rat intestinal epithelial (RIE-1) cells and 6 human colon cancer cell lines were examined. The effects of NaB on TGF-beta-induced Smad3 phosphorylation and plasminogen activator inhibitor-1 (PAI-1) and cyclooxygenase-2 (COX-2) gene expression were also examined in RIE-1 cells. Finally, the effects of NaB and TGF-beta on anchorage-independent growth were examined in Akt-transformed RIE-1 cells. NaB induced Smad3 in RIE-1 cells and in 4 human colon cancer cell lines. NaB enhanced TGF-beta-induced Smad3 phosphorylation and potentiated TGF-beta-induced PAI-1 expression. NaB and TGF-beta synergistically inhibited anchorage-independent growth of Akt-transformed RIE-1 cells. These results demonstrate that NaB induces Smad3 and potentiates TGF-beta signaling and its tumor suppressor activity in gut epithelial cells. Our data reveal a novel molecular mechanism that may explain in part the beneficial effects of dietary fiber in decreasing the risk of colon cancers.