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PKCiota promotes ovarian tumor progression through deregulation of cyclin E

A Nanos-Webb1, T Bui1, C Karakas1

  • 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Oncogene
|August 18, 2015
PubMed

Insights

Targeting the PI3K/PKCiota/cyclin E pathway shows promise for treating ovarian tumors. Inhibiting this pathway reduces cancer cell growth and improves survival in mouse models, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Epithelial ovarian tumors frequently relapse after chemotherapy, necessitating novel targeted therapies.
  • Overexpression of Protein Kinase C iota (PKCiota) and cyclin E is common in high-grade ovarian tumors, suggesting a potential therapeutic pathway.

Purpose of the Study:

  • To investigate the role of a phosphoinositide 3-kinase (PI3K)-dependent signaling pathway involving PKCiota in perpetuating cyclin E deregulation during ovarian tumorigenesis.
  • To explore the therapeutic potential of targeting the PI3K/PKCiota/cyclin E signaling axis in ovarian cancer.

Main Methods:

  • Correlation analysis of PKCiota and cyclin E expression in 19 ovarian cancer cell lines.
  • In vitro and in vivo studies using short hairpin RNA (shRNA) targeting PKCiota (shPKCiota) in ovarian cancer cells (IGROV, OVCAR-3).
  • Assessment of proliferation, cell cycle arrest, anchorage-independent growth, and xenograft mouse models. Reverse-phase protein array (RPPA) analysis and PI3K inhibitor treatment.

Main Results:

  • A positive correlation between PKCiota and cyclin E was observed in ovarian cancer cell lines.
  • PKCiota knockdown (shPKCiota) in serous ovarian cancer cells reduced proliferation, induced G1 arrest, and prolonged survival in xenograft models.
  • shPKCiota impaired anchorage-independent growth and acini formation, dependent on cyclin E expression. PI3K pathway activation correlated with phospho-PKCiota levels, and PI3K inhibitors reduced phospho-PKCiota and cyclin E.

Conclusions:

  • The PI3K/PKCiota/cyclin E signaling pathway is identified as a critical driver of ovarian tumorigenesis.
  • Targeting this pathway, particularly PKCiota, represents a promising therapeutic strategy for epithelial ovarian tumors.
  • Inhibition of PI3K effectively downregulates key components of this oncogenic signaling cascade.

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