The involvement of protein kinase C isoenzymes alpha, epsilon and zeta in the sensitivity to antitumor treatment and apoptosis induction.
In order to obtain additional information on the involvement of protein kinase C (PKC) isoenzymes in the resistance of cells to anticancer drugs and in the induction of apoptosis, we employed antisense oligonucleotides to PKC alpha and PKC zeta, CGP 53506, a new inhibitor of PKC alpha, and cells overexpressing PKC alpha, PKC epsilon and PKC zeta. We found that in HeLa cells which express PKC alpha and zeta, down-modulation of either PKC alpha or PKC zeta with antisense oligonucleotides induced apoptosis. The PKC alpha selective inhibitor CGP 53506 reduced the proliferation rate of PKC alpha overexpressing NIH3T3 cells more than that of wild-type cells and induced apoptosis, indicating that such a PKC alpha inhibitor may be useful in the treatment of tumors overexpressing PKC alpha such as glioblastomas. NIH3T3 cells overexpressing PKC alpha were more resistant, whereas NIH3T3 cells overexpressing PKC epsilon or PKC zeta were more sensitive to treatment with cis-platin, adriamycin or gamma-irradiation compared to parental NIH3T3 wild-type cells. The observed resistance and sensitization corresponded to the extent of apoptosis induced by these treatments. Alterations in the expression of p53, bcl-2 and bax in the PKC isoenzyme overexpressing cells indicate that these proteins may be involved in the different sensitivities of these cells.
Spitaler
M
M
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Wiesenhofer
B
B
Biedermann
V
V
Seppi
T
T
Zimmermann
J
J
Grunicke
H
H
Hofmann
J
J
D016475:3T3 Cells; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005720:Gamma Rays; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D011743:Pyrimidines / Q000494:pharmacology*; D013997:Time Factors; D000099221:Protein Kinase C zeta
D017304:Annexin A5; D002945:Cisplatin; D004317:Doxorubicin; D007527:Isoenzymes; D016376:Oligonucleotides, Antisense; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D011743:Pyrimidines; D000099221:Protein Kinase C zeta; C403962:CGP 53506; C497256:Prkce protein, mouse; C496628:PRKCA protein, human; C497255:PRKCE protein, human; C496630:Prkca protein, mouse