Protein Kinase Cι Activity Is Necessary for Bcr-Abl-mediated Resistance to Drug-induced Apoptosis*
- From the ‡Sealy Center for Oncology and Hematology and the Departments of ¶Pharmacology and ‖Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555-1048 and the §Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia
Abstract
K562 chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs, such as taxol, that induce cell death by apoptosis. This resistance 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 PKCι is necessary 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 demonstrate that treatment of K562 cells with taxol leads to sustained activation of PKCι. In contrast, Bcr-Abl-negative HL60 myeloid leukemia cells, which are sensitive to taxol-induced apoptosis, do not exhibit sustained PKCι activation in response to taxol. Treatment of K562 cells with tyrphostin AG957, a selective Bcr-Abl inhibitor, blocks taxol-induced PKCι activation and sensitizes these cells to taxol-induced apoptosis, indicating that PKCι is a relevant downstream target of Bcr-Abl-mediated resistance. Furthermore, expression of constitutively active PKCι by adenovirus-mediated gene transfer rescues AG957-treated K562 cells from taxol-induced apoptosis. Taken together, these results demonstrate that both Bcr-Abl and PKCι activity are necessary for apoptotic resistance in K562 cells. Furthermore, they identify PKCι as a critical downstream target of Bcr-Abl that is sufficient to mediate the anti-apoptotic effects of Bcr-Abl.
Footnotes
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↵* This work was supported in part by National Institutes of Health Grant CA56869 (to A. P. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵** Leukemia Society of America Scholar. To whom correspondence should be addressed: Sealy Center for Oncology & Hematology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1048.
- Abbreviations:
- CML
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chronic myelogenous leukemia
- PKC
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protein kinase C
- PI
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phosphatidylinositol
- GFP
-
green fluorescent protein.
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- Received November 3, 1998.
- Revision received December 9, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
