Protein Kinase Cδ is a downstream effector of oncogenic KRAS in lung tumors1
| Autor: | Symonds, Jennifer M., Ohm, Angela M., Carter, Cristan J., Heasley, Lynn E., Aly, Theresa A., Franklin, Wilbur A., Reyland, Mary E. |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Lung Neoplasms Cell Survival Immunoblotting Mice Nude Urethane Article Cell Line Mice Cell Movement Carcinoma Non-Small-Cell Lung Cell Line Tumor Animals Humans neoplasms Cell Proliferation Mice Knockout digestive system diseases respiratory tract diseases Tumor Burden Enzyme Activation Mice Inbred C57BL Protein Kinase C-delta Mutation ras Proteins Female RNA Interference Mitogen-Activated Protein Kinases |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|