Atypical Protein Kinase Cι Plays a Critical Role in Human Lung Cancer Cell Growth and Tumorigenicity

Abstract 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 aPKCι is highly expressed in human non-small cell lung cancer cell lines, whereas the closely related aPKC isozyme PKCζ is undetectable in these cells. Disruption of PKCι signaling reveals that PKCι 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 down-stream of PKCι demonstrates that Rac1 is a critical molecular target for PKCι-dependent transformation, whereas PKCι is not necessary for NFκB activation in vitro or in vivo. Expression of the PB1 domain of PKCι (PKCι-(1-113)) blocks PKCι-dependent Rac1 activity and inhibits cellular transformation indicating a role for this domain in the transforming activity of PKCι. Taken together, our data demonstrate that PKCι 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 PKCι may be an attractive molecular target for mechanism-based therapies for treatment of lung cancer.