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J. Biol. Chem., Vol. 277, Issue 38, 35305-35313, September 20, 2002
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From the University of Florida Shands Cancer Center and
Department of Anatomy & Cell Biology, University of Florida,
Gainesville, Florida 32610
The serine/threonine protein kinase C (PKC) has
been implicated in the regulation of drug resistance and cell survival
in many types of cancer cells. However, the one or more precise
mechanisms remain elusive. In this study, we have identified and
determined the mechanism by which PKC-
Protein Kinase C-
Promotes Survival of Lung Cancer Cells by
Suppressing Apoptosis through Dysregulation of the Mitochondrial
Caspase Pathway*
, a novel PKC isoform,
modulates drug resistance in lung cancer cells. Western blot analysis
demonstrates that expression of PKC-, but not other PKC isoforms, is
associated with the chemo-resistant phenotype of non-small cell lung
cancer (NSCLC) cell lines. Northern blotting and nuclear run-on
transcription analysis further reveals that the failure of expression
of PKC- in the chemo-sensitive phenotype of small cell lung cancer
(SCLC) cells results from transcriptional inactivation of the gene.
Importantly, forced expression of PKC- in NCI-H82 human SCLC cells
confers a significant resistance to the chemotherapeutic drugs,
etoposide and doxorubicin. Resistance is characterized by a significant reduction in apoptosis in PKC--expressing cells. Treatment of NCI-H82 cells with etoposide induces a series of
time-dependent events, including the release of cytochrome
c from the mitochondria to the cytosol, activation of
caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase
(PARP). All of these events are blocked by PKC- expression.
Furthermore, caspase-specific inhibitors, z-VAD-fmk and z-DEVD-fmk,
significantly attenuate the accumulation of sub-G1
population and block the PARP cleavage in response to etoposide. These
results suggest that PKC- prevents cells from undergoing apoptosis
through inhibition of the mitochondrial-dependent caspase
activation, thereby leading to cell survival. Finally, down-regulation
of PKC- expression by the antisense cDNA in NSCLC cells results
in increased sensitivity to etoposide. Taken together, our findings
suggest an important role for PKC- in regulating survival of lung
cancer cells.
*
This work was supported by National Institutes of Health
Grant R01-CA88815.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.
To whom correspondence should be addressed: University of Florida
Shands Cancer Center, 1600 S.W. Archer Rd., P. O. Box 100232, Gainesville, FL 32610-0232. Tel.: 352-846-1199; Fax: 352-392-5802; E-mail: lxiao@ufl.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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