Atypical Protein Kinase C[iota] 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.