The expression of ErbB proteins, together with heregulin, was found to be increased in colon cancer cells compared with normal mucosa, and heregulin-stimulated activation of ErbB signaling was observed to contribute to the proliferation of colon cancer cells. Butyrate produced during the fermentation of fiber by intestinal bacteria is known to exert diverse anticancer effects, including the induction of differentiation, cell cycle arrest and growth suppression in human colon cancer cells. In this study, we investigated whether butyrate affects the heregulin/ErbB-mediated proliferation of colon cancer cells. The growth of human CaCo-2 and SNU-C4 colon cancer cells, which express ErbB1-4 proteins, was stimulated by heregulin in a concentration-dependent manner. Pretreatment with sodium butyrate abolished heregulin-stimulated proliferation in both cell lines. Although butyrate did not alter ErbB protein expression and activation, it did block the prolonged activation of Akt and Erk1/2, which are known to be important ErbB downstream molecules mediating heregulin-stimulated proliferation. Our data suggest that the inhibitory effects of butyrate on the heregulin-stimulated proliferation of colorectal cancer cells are, in part, associated with the suppression of the Akt and Erk signaling pathway. Butyrate may act as a preventive and therapeutic agent in the progression of colorectal cancer through the regulation of heregulin-stimulated mitogenic signaling.

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