| First Author | Symonds JM | Year | 2011 |
| Journal | Cancer Res | Volume | 71 |
| Issue | 6 | Pages | 2087-97 |
| PubMed ID | 21335545 | Mgi Jnum | J:170465 |
| Mgi Id | MGI:4946545 | Doi | 10.1158/0008-5472.CAN-10-1511 |
| Citation | Symonds JM, et al. (2011) Protein Kinase C {delta} Is a Downstream Effector of Oncogenic K-ras in Lung Tumors. Cancer Res 71(6):2087-97 |
| abstractText | 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 delta (PKCdelta) 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 PKCdelta-deficient knockout (deltaKO) mice compared with wild-type (deltaWT) mice. deltaKO tumors are smaller and showed reduced proliferation. DNA sequencing indicated that all deltaWT tumors had activating mutations in KRAS, whereas only 69% of deltaKO tumors did, suggesting that PKCdelta 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 PKCdelta 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, PKCdelta 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 PKCdelta in tumor cells depends on a specific oncogenic context, as loss of PKCdelta in NSCLC cells suppressed transformed growth only in cells dependent on oncogenic K-ras for proliferation and survival. Cancer Res; 71(6); 2087-97. (c)2011 AACR. |
