Distinct PKC isozymes regulate bufalin-induced differentiation and apoptosis in human monocytic cells.
Bufalin, an Na(+)-K(+)-ATPase inhibitor, simultaneously induced cell differentiation and apoptosis in human monocytic leukemia THP-1 cells. In this study, we investigated the regulatory role of protein kinase C (PKC) isozymes in bufalin-induced cell differentiation and apoptosis. A PKC-specific but isozyme-nonselective inhibitor, Ro-31-8220, and a cPKC selective inhibitor, Gö-6976, caused significant attenuation of bufalin-induced interleukin-1beta (IL-1beta) gene expression, a mature monocytic marker, indicating that cPKC participates in the bufalin-induced cell differentiation. On the other hand, cPKCbeta- and nPKCdelta-defective THP-1/TPA cells displayed strong resistance to the bufalin-induced DNA ladder formation. Rottlerin, an nPKCdelta-specific inhibitor, partially attenuated preapoptotic effects of bufalin, such as the limited proteolysis of nPKCdelta and poly(ADP-ribose) polymerase and the cell staining by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, suggesting that nPKCdelta is involved, at least in part, in bufalin-induced apoptosis. In contrast, Gö-6976 and rottlerin significantly augmented bufalin-induced apoptosis and differentiation, respectively. The findings suggest that bufalin-induced cell differentiation and apoptosis are interlinked and that distinct PKC isozymes are involved in the fate of the cell.
Kurosawa
M
M
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo 142-8555, Japan.
Tani
Y
Y
Nishimura
S
S
Numazawa
S
S
Yoshida
T
T
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002018:Bufanolides / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D009000:Monocytes / Q000166:cytology* / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D002018:Bufanolides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011493:Protein Kinase C; C022777:bufalin