Atypical protein kinase Cι, is an oncogene in human non-small cell lung cancer

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 PKC iota is overexpressed in human non-small cell lung cancer (NSCLC) cells and that PKC iota 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 PKC iota is an oncogene in NSCLC based on the following criteria: (a) aPKC iota is overexpressed in the vast majority of primary NSCLC tumors; (b) tumor PKC iota expression levels predict poor survival in patients with NSCLC; (c) the PKC iota gene is frequently amplified in established NSCLC cell lines and primary NSCLC tumors; (d) gene amplification drives PKC iota expression in NSCLC cell lines and primary NSCLC tumors; and (e) disruption of PKC iota signaling with a dominant negative PKC iota allele blocks the transformed growth of human NSCLC cells harboring PKC iota gene amplification. Taken together, our data provide conclusive evidence that PKC iota is required for the transformed growth of NSCLC cells and that the PKC iota gene is a target for tumor-specific genetic alteration by amplification. Interestingly, PKC iota expression predicts poor survival in NSCLC patients independent of tumor stage. Therefore, PKC iota expression profiling may be useful in identifying early-stage NSCLC patients at elevated risk of relapse. Our functional data indicate that PKC iota is an attractive target for development of novel, mechanism-based therapeutics to treat NSCLC.