Atypical Protein Kinase Cι Is an Oncogene in Human Non–Small Cell Lung Cancer

Abstract

Protein kinase C (PKC) isozymes have long been implicated in carcinogenesis. However, little is known about the functional significance of these enzymes in human cancer. We recently showed that the atypical PKC (aPKC) isozyme PKCι is overexpressed in human non–small cell lung cancer (NSCLC) cells and that PKCι plays a critical role in the transformed growth of the human lung adenocarcinoma A549 cell line in vitro and tumorigenicity in vivo. Here we provide compelling evidence that PKCι is an oncogene in NSCLC based on the following criteria: (a) aPKCι is overexpressed in the vast majority of primary NSCLC tumors; (b) tumor PKCι expression levels predict poor survival in patients with NSCLC; (c) the PKCι gene is frequently amplified in established NSCLC cell lines and primary NSCLC tumors; (d) gene amplification drives PKCι expression in NSCLC cell lines and primary NSCLC tumors; and (e) disruption of PKCι signaling with a dominant negative PKCι allele blocks the transformed growth of human NSCLC cells harboring PKCι gene amplification. Taken together, our data provide conclusive evidence that PKCι is required for the transformed growth of NSCLC cells and that the PKCι gene is a target for tumor-specific genetic alteration by amplification. Interestingly, PKCι expression predicts poor survival in NSCLC patients independent of tumor stage. Therefore, PKCι expression profiling may be useful in identifying early-stage NSCLC patients at elevated risk of relapse. Our functional data indicate that PKCι is an attractive target for development of novel, mechanism-based therapeutics to treat NSCLC.