PKCiota promotes ovarian tumor progression through deregulation of cyclin e

A. Nanos-Webb, T. Bui, C. Karakas, D. Zhang, J. P.W. Carey, G. B. Mills, K. K. Hunt, K. Keyomarsi

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The high frequency of relapse of epithelial ovarian tumors treated with standard chemotherapy has highlighted the necessity to identify targeted therapies that can improve patient outcomes. The dynamic relationship between cyclin E and PKCiota frequent overexpression in high-grade ovarian tumors poses a novel pathway for therapeutic investigation. We hypothesized that a phosphoinositide 3-kinase (PI3K)-dependent signaling pathway activating PKCiota perpetuates cyclin E deregulation during ovarian tumorigenesis. We observed a positive correlation between PKCiota and cyclin E in a panel of 19 ovarian cancer cell lines. Modulation of cyclin E had no effect on PKCiota knockdown/overexpression; however, PKCiota differentially regulated cyclin E expression. In the serous ovarian cancer cells (IGROV and OVCAR-3), shPKCiota decreased proliferation, caused a G1 arrest and significantly prolonged overall survival in xenograft mouse models. In vitro, shPKCiota decreased the ability of IGROV cells to grow under anchorage-independent conditions and form aberrant acini, which was dependent on Ad-cyclin E or Ad-LMW-E expression. Reverse-phase protein array analysis of PKCiota wild-type, catalytic active, dominant-negative protein isoforms strengthened the association between phospho-PKCiota levels and PI3K pathway activation. Inhibitors of PI3K coordinately decreased phospho-PKCiota and cyclin E protein levels. In conclusion, we have identified a PI3K/PKCiota/cyclin E signaling pathway as a therapeutic target during ovarian tumorigenesis.

Original languageEnglish (US)
Pages (from-to)2428-2440
Number of pages13
JournalOncogene
Volume35
Issue number19
DOIs
StatePublished - May 12 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Nanos-Webb, A., Bui, T., Karakas, C., Zhang, D., Carey, J. P. W., Mills, G. B., Hunt, K. K., & Keyomarsi, K. (2016). PKCiota promotes ovarian tumor progression through deregulation of cyclin e. Oncogene, 35(19), 2428-2440. https://doi.org/10.1038/onc.2015.301