Atypical protein kinase Cι plays a critical role in human lung cancer cell growth and tumorigenicity

Atypical protein kinase C ( aPKC) isozymes function in epithelial cell polarity, proliferation, and survival and have been implicated in cellular transformation. However, the role of these enzymes in human cancer is largely unexplored. Here, we report that aPKC iota is highly expressed in human non-small cell lung cancer cell lines, whereas the closely related aPKC isozyme PKC iota is undetectable in these cells. Disruption of PKC iota signaling reveals that PKC iota is dispensable for adherent growth of non-small cell lung cancer cells but is required for transformed growth in soft agar in vitro and for tumorigenicity in vivo. Molecular dissection of signaling downstream of PKC iota demonstrates that Rac1 is a critical molecular target for PKC iota-dependent transformation, whereas PKC iota is not necessary for NF kappa B activation in vitro or in vivo. Expression of the PB1 domain of PKC iota (PKC iota- (1-113)) blocks PKC iota-dependent Rac1 activity and inhibits cellular transformation indicating a role for this domain in the transforming activity of PKC iota. Taken together, our data demonstrate that PKC iota is a critical lung cancer gene that activates a Rac1 -> Pak -> Mek1,2 -> Erk1,2 signaling pathway required for transformed growth. Our data indicate that PKC iota may be an attractive molecular target for mechanism-based therapies for treatment of lung cancer.