title: Proteins kinase Cɛ is required for non-small cell lung carcinoma growth and regulates the expression of apoptotic genes.
abstract: Protein kinase C (PKC)ɛ, a member of the novel PKC family, has key roles in mitogenesis and survival in normal and cancer cells. PKCɛ is frequently overexpressed in epithelial cancers, particularly in lung cancer. Using a short-hairpin RNA approach, here we established that PKCɛ is required for non-small cell lung carcinoma (NSCLC) growth in vitro as well as tumor growth when inoculated into athymic mice. Moreover, sustained delivery of a PKCɛ-selective inhibitor peptide, ɛV1-2, reduced xenograft growth in mice. Both RNA interference depletion and pharmacological inhibition of PKCɛ caused a marked elevation in the number of apoptotic cells in NSCLC tumors. PKCɛ-depleted NSCLC cells show elevated expression of pro-apoptotic proteins of the Bcl-2 family, caspase recruitment domain-containing proteins and tumor necrosis factor ligands/receptor superfamily members. Moreover, a Gene Set Enrichment Analysis revealed that a vast majority of the genes changed in PKCɛ-depleted cells were also deregulated in human NSCLC. Our results strongly suggest that PKCɛ is required for NSCLC cell survival and maintenance of NSCLC tumor growth. Therefore, PKCɛ may represent an attractive therapeutic target for NSCLC.
authors: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: M C
authors: MC
authors: Caino
authors: C
authors: C
authors: Lopez-Haber
authors: J
authors: J
authors: Kim
authors: D
authors: D
authors: Mochly-Rosen
authors: M G
authors: MG
authors: Kazanietz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D019254:Genes, bcl-2; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000494:pharmacology; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; C448318:epsilonV1-2 peptide; D051744:Protein Kinase C-epsilon