Protein Kinase C Involvement in Deoxycholate-Induced Apoptosis in Human Gastric Cells
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Bile acids, such as deoxycholic acid (DC), are known to mediate some of their actions by differentially activating various protein kinase C (PKC) isoforms. This study confirms that DC induces apoptosis in gastric epithelial cells through PARP and caspase cascade activation, and examined the role of PKC in DC-induced apoptosis. We found increased activation of PKC in membrane fractions in response to DC that was concentration and time related. The PKC (βI) isoform expression increased with translocation into the cell membrane fraction after DC (300 μ M) stimulation. In contrast, PKCε expression markedly decreased in response to DC treatment in a time- and concentration-dependent manner. In addition, this process was regulated by caspases, since the pan-caspase inhibitor z-VAD-fmk and caspase-3-, -6-, and -9–specific inhibitors prevented PKC (βI) and (ε ɛ processing induced by DC. Treatment with the caspase-8–specific inhibitor, however, did not affect expression of either PKC isoform. No significant differences in the apoptotic response were observed when PKC (ɛ) overexpressed cells were exposed to DC in the presence of calcium-dependent conventional PKC inhibitors (Gö 6850 or Gö 6976). Our findings demonstrate that PKC is activated in gastric epithelial cells treated with DC with the PKC (βI) and PKC (ɛ) isoforms being particularly involved in this process. The processing of PKC (βI and ε) was shown to be closely regulated by caspases; however, modulations in PKC isoform concentrations by themselves have no effect on the apoptotic death of gastric mucosal cells induced by DC.
Key Wordscaspases cell signaling gastric epithelial injury
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- 3.Miller TA, Victor BE: Gastritis and gastric ulcer. In Surgical Treatment of Digestive Disease, 2nd ed. Moody FG, Carey LC, Jones RS, Kelly JA, Nahrwold DL, Skinner DB (eds). Chicago, Year Book Medical, 1989, pp. 174–196Google Scholar
- 4.Kokoska ER, Smith GS,Wolff AB, Deshpande Y, Rieckenberg CL, Banan A, Miller TA: Role of calcium in adaptive cytoprotection and cell injury induced by deoxycholate in human gastric cells. Am J Physiol 275:G322–G330, 1998Google Scholar
- 10.Jones BA, Rao YP, Stravitz RT, Gores GJ: Bile salt-induced apoptosis of hepatocytes involves activation of protein kinase C. Am J Physiol Gastrointest Liver Physiol 5:G1109–G1115, 1997Google Scholar
- 14.Newton AC: Protein kinase C: structure, function, and regulation. J Biol Chem 48:28495–28498, 1995Google Scholar
- 18.18. Zhu GH, Wong BC, Slosberg ED, Jiang SH, Kung HF, Soh JW, Weinstein IB: Over-expression of protein kinase C-β1 isoenzyme suppresses indomethacin-induced apoptosis in gastric epithelial cells. Gastroenterology 118:507–514, 2000Google Scholar