Altered protein kinase C (PKC) isoforms in non-small cell lung cancer cells: PKCdelta promotes cellular survival and chemotherapeutic resistance.
Drugs that target protein kinase C (PKC) are now being evaluated in patients with non-small cell lung cancer (NSCLC), but the role of PKC in NSCLC cells remains unclear. We report here that NSCLC cell lines show enhanced phosphorylation and altered expression of specific PKC isoforms compared with normal lung epithelial cells. PKC inhibition variably increased apoptosis, with rottlerin, a PKCdelta inhibitor, being most effective and potentiating chemotherapy-induced apoptosis, especially with trastuzumab. Consistent with PKCdelta being anti-apoptotic in NSCLC cells, transient transfection of a kinase-dead mutant of PKCdelta increased apoptosis and potentiated chemotherapy-induced apoptosis. Our studies provide a rationale for targeting PKC isoforms in NSCLC cells, especially PKCdelta.
Clark
Amy S
AS
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.
West
Kip A
KA
Blumberg
Peter M
PM
Dennis
Phillip A
PA
D000098:Acetophenones / Q000008:administration & dosage / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051745:Protein Kinase C-delta; D014162:Transfection; D000068878:Trastuzumab
D000098:Acetophenones; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C085746:rottlerin; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D000068878:Trastuzumab