Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium

Alice H. Hsu, Michelle A. Lum, Kang Sup Shim, Peter J. Frederick, Carl D. Morrison, Baojiang Chen, Subodh M. Lele, Yuri M. Sheinin, Takiko Daikoku, Sudhansu K. Dey, Gustavo Leone, Adrian R. Black, Jennifer D. Black

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Protein kinase C (PKC) isozymes are commonly recognized as oncoproteins based on their activation by tumor-promoting phorbol esters. However, accumulating evidence indicates that PKCs can be inhibitory in some cancers, with recent findings propelling a shift in focus to understanding tumor suppressive functions of these enzymes. Here, we report that PKCα acts as a tumor suppressor in PI3K/AKT-driven endometrial cancer. Transcriptional suppression of PKCα is observed in human endometrial tumors in association with aggressive disease and poor prognosis. In murine models, loss of PKCα is rate limiting for endometrial tumor initiation. PKCα tumor suppression involves PP2A-family-dependent inactivation of AKT, which can occur even in the context of genetic hyperactivation of PI3K/AKT signaling by coincident mutations in PTEN, PIK3CA, and/or PIK3R1. Together, our data point to PKCα as a crucial tumor suppressor in the endometrium, with deregulation of a PKCα→PP2A/PP2A-like phosphatase signaling axis contributing to robust AKT activation and enhanced endometrial tumorigenesis. Hsu et al. find that PKCα is frequently lost in human and murine endometrial tumors and that PKCα deficiency enhances PI3K/AKT-driven endometrial neoplasia. PKCα suppresses aberrant AKT activity via a PP2A family phosphatase-dependent mechanism. Thus, PKCα loss appears to cooperate with PI3K/AKT perturbations to hyperactivate AKT and promote endometrial tumorigenesis.

Original languageEnglish (US)
Pages (from-to)655-669
Number of pages15
JournalCell Reports
Volume24
Issue number3
DOIs
StatePublished - Jul 17 2018

Keywords

  • AKT
  • Id1
  • PI3K
  • PKC
  • PKCα
  • PP2A family
  • PTEN
  • endometrial cancer
  • endometrium
  • tumor suppression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Hsu, A. H., Lum, M. A., Shim, K. S., Frederick, P. J., Morrison, C. D., Chen, B., Lele, S. M., Sheinin, Y. M., Daikoku, T., Dey, S. K., Leone, G., Black, A. R., & Black, J. D. (2018). Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium. Cell Reports, 24(3), 655-669. https://doi.org/10.1016/j.celrep.2018.06.067