1. ¹Department of Immunology, The Medical School, Birmingham University, Birmingham B15 2TT, UK
2. ²Department of Anatomy, The Medical School, Birmingham University, Birmingham B15 2TT, UK

Correspondence: Dr JM Lord, E-mail: J.M.Lord@bham.ac.uk

³Contributed equally to the work presented here.

Received 22 July 2002; Revised 6 November 2002; Accepted 2 December 2002.

Abstract

Butyrate, produced in the colon by fermentation of dietary fibre, induces apoptosis in colon adenoma and cancer cell lines, which may contribute to protection against colorectal cancer. However, butyrate is present in the colon along with other dietary factors, including unconjugated bile acids, which are tumour promoters. We have shown previously that the proapoptotic effects of butyrate on AA/C1 human adenoma cells were reduced in the presence of bile acids. To determine the cellular basis of this interaction, we examined the effects of butyrate and the secondary bile acid ursodeoxycholic acid (UDCA) on signalling pathways known to regulate apoptosis using AA/C1 cells. Butyrate activated PKC- and p38 MAP (mitogen-activated protein) kinase, whereas UDCA activated PKC- and p42/44 MAP kinase. Butyrate treatment also resulted in the caspase-3-mediated proteolysis of PKC-. Butyrate-induced apoptosis was reduced by inhibitors of PKC- (Rottlerin), p38 MAP kinase (SB202190) and caspase 3 (DEVD-fmk), whereas the proliferative/survival effects of UDCA were blocked by inhibitors of PKC- (Gö6976) and MEK 1 (PD98059). The effects of butyrate and bile acids are therefore mediated by the differential activation of signalling pathways that are known to regulate apoptosis.