Protein kinase C iota activity is necessary for Bcr-Abl-mediated resistance to drug-induced apoptosis

K562 chronic myelogenous leukemia cells are highly resistant to chemotherap eutic drugs, such as taxol, that induce cell death by apoptosis. This resis tance is mediated by the chimeric tyrosine kinase oncogene Bcr-Abl. However , little is known about the mechanism by which Bcr-Abl protects K562 cells from apoptosis. We recently demonstrated that expression of PKC iota is nec essary for the resistance of K562 cells to taxol-induced apoptosis (Murray, N. R., and Fields, A. P. (1997) J. Biol. Chem. 272, 27521-27524). We now d emonstrate that treatment of K562 cells with taxol leads to sustained activ ation of PKC iota. In contrast, Bcr-Abl-negative HL60 myeloid leukemia cell s, which are sensitive to taxol-induced apoptosis, do not exhibit sustained PKC iota activation in response to taxol, Treatment of K562 cells with tyr phostin AG957, a selective Bcr-Abl inhibitor, blocks taxol-induced PKC iota activation and sensitizes these cells to taxol-induced apoptosis, indicati ng that PKC iota is a relevant downstream target of Bcr-Abl-mediated resist ance. Furthermore, expression of constitutively active PKC iota by adenovir us-mediated gene transfer rescues AG957-treated K562 cells from taxol-induc ed apoptosis. Taken together, these results demonstrate that both Bcr-Abl a nd PKC iota activity are necessary for apoptotic resistance in K562 cells, Furthermore, they identify PKC iota as a critical downstream target of Bcr- Abl that is sufficient to mediate the anti-apoptotic effects of Bcr-Abl.