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


BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Nguyen
Khoa A
KA
Department of Surgery, University of Texas Medical Branch, Galveston, 77555, USA.
Cao
Yanna
Y
Chen
Justin R
JR
Townsend
Courtney M
CM
Ko
Tien C
TC
D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000517:prevention & control; D004043:Dietary Fiber / Q000627:therapeutic use; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000502:physiology; D051381:Rats; D015398:Signal Transduction; D051900:Smad3 Protein / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000502:physiology*
D004043:Dietary Fiber; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D020148:Butyric Acid