Atypical protein kinase Ciota 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 aPKCiota is highly expressed in human non-small cell lung cancer cell lines, whereas the closely related aPKC isozyme PKCzeta is undetectable in these cells. Disruption of PKCiota signaling reveals that PKCiota 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 PKCiota demonstrates that Rac1 is a critical molecular target for PKCiota-dependent transformation, whereas PKCiota is not necessary for NFkappaB activation in vitro or in vivo. Expression of the PB1 domain of PKCiota (PKCiota-(1-113)) blocks PKCiota-dependent Rac1 activity and inhibits cellular transformation indicating a role for this domain in the transforming activity of PKCiota. Taken together, our data demonstrate that PKCiota 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 PKCiota may be an attractive molecular target for mechanism-based therapies for treatment of lung cancer.
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224, USA.
Roderick P
RP
Regala
Capella
C
Weems
Lee
L
Jamieson
John A
JA
Copland
E Aubrey
EA
Thompson
Alan P
AP
Fields
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000099293:Protein Kinase C-lambda
D007527:Isoenzymes; D016328:NF-kappa B; D011493:Protein Kinase C; D020830:rac1 GTP-Binding Protein; D000099293:Protein Kinase C-lambda