title: PKCι maintains a tumor-initiating cell phenotype that is required for ovarian tumorigenesis.
abstract: Protein kinase Cι (PKCι) has oncogenic potential and is an attractive therapeutic target for treatment of lung cancer, particularly those tumors that express elevated PKCι. However, whether PKCι is a viable target in ovarian cancer is unknown, and virtually nothing is known about the mechanism by which PKCι drives ovarian tumorigenesis. Here, it is demonstrated that PKCι maintains a tumor-initiating cell (TIC) phenotype that drives ovarian tumorigenesis. A highly tumorigenic population of cells from human ovarian cancer cell lines exhibit cancer stem-like TIC properties, including self-renewal, clonal expansion, expression of stem-related genes, enhanced transformed growth in vitro, and aggressive tumor-initiating activity in vivo. Genetic disruption of PKCι inhibits the proliferation, clonal expansion, anchorage-independent growth, and enhanced tumorigenic properties of ovarian TICs. Biochemical analysis demonstrates that PKCι acts through its oncogenic partner Ect2 to activate a MEK/ERK signaling axis that drives the ovarian TIC phenotype. Genomic analysis reveals that PKCι and Ect2 are coordinately amplified and overexpressed in the majority of primary ovarian serous tumors, and these tumors exhibit evidence of an active PKCι-Ect2 signaling axis in vivo. Finally, this study reveals that auranofin, a potent and selective inhibitor of oncogenic PKCι signaling, inhibits the tumorigenic properties of ovarian TIC cells in vitro and in vivo. These data demonstrate that PKCι is required for a TIC phenotype in ovarian cancer, and that auranofin is an attractive therapeutic option to target deadly ovarian TICs in ovarian cancer patients.
  
  
  CONCLUSIONS
  PKCι drives a tumor-initiating cell phenotype in ovarian cancer cells that can be therapeutically targeted with auranofin, a small molecule inhibitor of PKCι signaling.
authors.affiliation: Griffin Cancer Research Building, Rm. 212, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224. fields.alan@mayo.edu.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.forename: Kristen S
authors.initials: KS
authors.lastname: Hill
authors.forename: Alan P
authors.initials: AP
authors.lastname: Fields
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001310:Auranofin / Q000494:pharmacology; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000099293:Protein Kinase C-lambda
chemical_list: D000970:Antineoplastic Agents; D001310:Auranofin; D007527:Isoenzymes; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D000099293:Protein Kinase C-lambda