title: Protein kinase C δ is a downstream effector of oncogenic K-ras in lung tumors.
abstract: Oncogenic activation of K-ras occurs commonly in non-small cell lung cancer (NSCLC), but strategies to therapeutically target this pathway have been challenging to develop. Information about downstream effectors of K-ras remains incomplete, and tractable targets are yet to be defined. In this study, we investigated the role of protein kinase C δ (PKCδ) in K-ras-dependent lung tumorigenesis by using a mouse carcinogen model and human NSCLC cells. The incidence of urethane-induced lung tumors was decreased by 69% in PKCδ-deficient knockout (δKO) mice compared with wild-type (δWT) mice. δKO tumors are smaller and showed reduced proliferation. DNA sequencing indicated that all δWT tumors had activating mutations in KRAS, whereas only 69% of δKO tumors did, suggesting that PKCδ acts as a tumor promoter downstream of oncogenic K-ras while acting as a tumor suppressor in other oncogenic contexts. Similar results were obtained in a panel of NSCLC cell lines with oncogenic K-ras but which differ in their dependence on K-ras for survival. RNA interference-mediated attenuation of PKCδ inhibited anchorage-independent growth, invasion, migration, and tumorigenesis in K-ras-dependent cells. These effects were associated with suppression of mitogen-activated protein kinase pathway activation. In contrast, PKCδ attenuation enhanced anchorage-independent growth, invasion, and migration in NSCLC cells that were either K-ras-independent or that had WT KRAS. Unexpectedly, our studies indicate that the function of PKCδ in tumor cells depends on a specific oncogenic context, as loss of PKCδ in NSCLC cells suppressed transformed growth only in cells dependent on oncogenic K-ras for proliferation and survival.
authors.affiliation: Program in Cancer Biology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Symonds
authors.forename: Angela M
authors.initials: AM
authors.lastname: Ohm
authors.forename: Cristan J
authors.initials: CJ
authors.lastname: Carter
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Heasley
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Boyle
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Mary E
authors.initials: ME
authors.lastname: Reyland
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D051745:Protein Kinase C-delta / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D047368:Tumor Burden; D014520:Urethane; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014520:Urethane; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins