PKCeta confers protection against apoptosis by inhibiting the pro-apoptotic JNK activity in MCF-7 cells.
Apoptosis is frequently regulated by different protein kinases including protein kinase C family enzymes. Both inhibitory and stimulatory effects were demonstrated for several of the different PKC isoforms. Here we show that the novel PKC isoform, PKCeta, confers protection against apoptosis induced by the DNA damaging agents, UVC irradiation and the anti-cancer drug--Camptothecin, of the breast epithelial adenocarcinoma MCF-7 cells. The induced expression of PKCeta in MCF-7 cells, under the control of the tetracycline-responsive promoter, resulted in increased cell survival and inhibition of cleavage of the apoptotic marker PARP-1. Activation of caspase-7 and 9 and the release of cytochrome c were also inhibited by the inducible expression of PKCeta. Furthermore, JNK activity, required for apoptosis in MCF-7, as indicated by the inhibition of both caspase-7 cleavage and cytochrome c release from the mitochondria in the presence of the JNK inhibitor SP600125, was also suppressed by PKCeta expression. Hence, in contrast to most PKC isoforms enhancing JNK activation, our studies show that PKCeta is an anti-apoptotic protein, acting as a negative regulator of JNK activity. Thus, PKCeta could represent a target for intervention aimed to reduce resistance to anti-cancer treatments.
Rotem-Dai
Noa
N
The Schraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and the Cancer Research Center, Ben-Gurion University, Beer Sheva, Israel.
Oberkovitz
Galia
G
Abu-Ghanem
Sara
S
Livneh
Etta
E
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism*; D002166:Camptothecin / Q000494:pharmacology; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D014466:Ultraviolet Rays
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C081975:protein kinase C eta; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D053179:Caspase 7; D002166:Camptothecin