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

Evi1 is a survival factor which conveys resistance to both TGFβ- and taxol-mediated cell death via PI3K/AKT

“…We have shown that PKCi is an oncogene that is activated by amplification in squamous cell carcinoma of the lung (Regala et al, 2005a). We have also shown that PKC plays a critical role in transformed growth (Zhang et al, 2004;Regala et al, 2005b), but does not appear to function as a survival gene. In contrast, our present results show that Evi1 is a survival gene in human colon cancers that have undergone amplification of the 3q26 locus.…”

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…Subsequent interaction of PAR1 with 14-3-3 dissociates PAR1 from the plasma membrane, thereby preventing the distribution of PAR1 to the apical membrane domain. Gene amplification and elevated activity of aPKC, which downregulates PAR1 functions, have also been reported in ovarian, lung and colon carcinomas (Murray et al, 2004;Eder et al, 2005;Regala et al, 2005).…”

Repression of cancer cell senescence by PKCι

“…In glioblastoma, PKCi represses apoptosis and promotes invasion (Baldwin et al, 2006(Baldwin et al, , 2008. PKCi also has a key role in the pathogenesis of lung, ovarian and pancreatic cancer (Eder et al, 2005;Regala et al, 2005;Zhang et al, 2006). Several previous studies have provided evidence for a role for the PI-3-kinase pathway in senescence.…”