Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma cells: differential activation of PKC and MAP kinases.
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-delta and p38 MAP (mitogen-activated protein) kinase, whereas UDCA activated PKC-alpha and p42/44 MAP kinase. Butyrate treatment also resulted in the caspase-3-mediated proteolysis of PKC-delta. Butyrate-induced apoptosis was reduced by inhibitors of PKC-delta (Rottlerin), p38 MAP kinase (SB202190) and caspase 3 (DEVD-fmk), whereas the proliferative/survival effects of UDCA were blocked by inhibitors of PKC-alpha (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.
McMillan
L
L
Department of Immunology, The Medical School, Birmingham University, UK.
Butcher
S K
SK
Pongracz
J
J
Lord
J M
JM
D000236:Adenoma / Q000201:enzymology / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects*; D020148:Butyric Acid / Q000494:pharmacology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007527:Isoenzymes; D020148:Butyric Acid; D014580:Ursodeoxycholic Acid; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3