PKCi maintains a tumor-initiating cell phenotype that is required for ovarian tumorigenesis

Yin Wang, Kristen S. Hill, Alan P Fields

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Protein kinase Ci (PKCi) has oncogenic potential and is an attractive therapeutic target for treatment of lung cancer, particularly those tumors that express elevated PKCi. However, whether PKCi is a viable target in ovarian cancer is unknown, and virtually nothing is known about the mechanism by which PKCi drives ovarian tumorigenesis. Here, it is demonstrated that PKCi 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 PKCi inhibits the proliferation, clonal expansion, anchorage-independent growth, and enhanced tumorigenic properties of ovarian TICs. Biochemical analysis demonstrates that PKCi acts through its oncogenic partner Ect2 to activate a MEK/ERK signaling axis that drives the ovarian TIC phenotype. Genomic analysis reveals that PKCi and Ect2 are coordinately amplified and overexpressed in the majority of primary ovarian serous tumors, and these tumors exhibit evidence of an active PKCi-Ect2 signaling axis in vivo. Finally, this study reveals that auranofin, a potent and selective inhibitor of oncogenic PKCi signaling, inhibits the tumorigenic properties of ovarian TIC cells in vitro and.

Original languageEnglish (US)
Pages (from-to)1624-1635
Number of pages12
JournalMolecular Cancer Research
Volume11
Issue number12
DOIs
StatePublished - Dec 2013

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Neoplastic Stem Cells
Protein Kinases
Carcinogenesis
Phenotype
Neoplasms
Ovarian Neoplasms
Auranofin
Mitogen-Activated Protein Kinase Kinases
Protein Kinase Inhibitors
Growth
Lung Neoplasms
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

PKCi maintains a tumor-initiating cell phenotype that is required for ovarian tumorigenesis. / Wang, Yin; Hill, Kristen S.; Fields, Alan P.

In: Molecular Cancer Research, Vol. 11, No. 12, 12.2013, p. 1624-1635.

Research output: Contribution to journalArticle

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