Molecular and Cellular Pathobiology Protein Kinase C d Is a Downstream Effector of Oncogenic K-ras in Lung Tumors

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 d (PKCd) 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 PKCd-deficient knockout (dKO) mice compared with wild-type (dWT) mice. dKO tumors are smaller and showed reduced proliferation. DNA sequencing indicated that all dWT tumors had activating mutations in KRAS, whereas only 69% of dKO tumors did, suggesting that PKCd 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 PKCd 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, PKCd 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 PKCd in tumor cells depends on a specific oncogenic context, as loss of PKCd in NSCLC cells suppressed transformed growth only in cells dependent on oncogenic K-ras for proliferation and survival. Cancer Res; 71(6); 2087–97. 2011 AACR.