Butyrate-induced differentiation of colon cancer cells is PKC and JNK dependent.
Butyric acid, a short-chain fatty acid physiologically present in human large gut, is derived from bacterial fermentation of complex carbohydrates. It has been shown to reduce the growth and motility of colon cancer cell lines and to induce cell differentiation and apoptosis. Apoptosis is considered a result of normal colonocyte terminal differentiation in vivo. The aim of this study was to characterize the cellular mechanisms regulating differentiation of colon cancer cells stimulated with sodium butyrate (NaB). The two human colon cancer cell lines Caco-2 and HT-29 were treated with NaB at physiologically relevant concentrations. Alkaline phosphatase (ALP) activity, a marker of colonocyte differentiation, was increased 48 hr after treatment with 1 mM NaB. Higher doses of NaB (5 and 10 mM) induced apoptosis of the cells and failed to stimulate the colonocyte differentiation. Therefore, we assumed that butyrate augments cell differentiation and induces apoptosis, acting via various intracellular mechanisms, and butyrate-mediated programmed cell death cannot be considered a consequence of colonocyte terminal differentiation. The effect of NaB on ALP activity was significantly attenuated in the presence of inhibitors of protein kinase C and JNK. Inhibition of MEK-ERK signal transduction pathways augmented the impact of butyrate on colonocyte differentiation. These results suggest that butyrate could influence the colonocyte differentiation via modulation of the activity of cellular protein kinases and signal transduction.
Orchel
Arkadiusz
A
Department of Biopharmacy, Medical University of Silesia, 41-200 Sosnowiec, Poland. aorchel@slam.katowice.pl
Dzierzewicz
Zofia
Z
Parfiniewicz
Beata
B
Weglarz
Ludmiła
L
Wilczok
Tadeusz
T
D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology*; D018938:Caco-2 Cells / Q000187:drug effects / Q000201:enzymology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms; D004789:Enzyme Activation / Q000187:drug effects; D019073:HT29 Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D002087:Butyrates; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases