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

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

  2. Author Address

    Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA.Ohio State Univ, Coll Med, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA.Roswell Pk Comprehens Canc Ctr, Dept Gynecol Oncol, Buffalo, NY 14263 USA.Roswell Pk Comprehens Canc Ctr, Dept Pathol & Lab Med, Buffalo, NY 14263 USA.Univ Nebraska Med Ctr, Dept Biostat, Omaha, NE 68198 USA.Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA.Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH 45229 USA.NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA.Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Biostat & Data Sci, Austin Reg Campus, Austin, TX 78701 USA.Univ Minnesota, Dept Lab Med & Pathol, Sch Med, Minneapolis, MN 55455 USA.Kanazawa Univ, Div Transgen Anim Sci, Inst Expt Anim, Kanazawa, Ishikawa 9208640, Japan.Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA.
    1. Year: 2018
    2. Date: Jul 17
  2. Journal: CELL REPORTS
  3. CELL PRESS,
    1. 24
    2. 3
    3. Pages: 655-669
  5. Type of Article: Article
  6. ISSN: 2211-1247
  1. 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 PKC alpha acts as a tumor suppressor in PI3K/AKT-driven endometrial cancer. Transcriptional suppression of PKC alpha is observed in human endometrial tumors in association with aggressive disease and poor prognosis. In murine models, loss of PKC alpha is rate limiting for endometrial tumor initiation. PKC alpha 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 PKC alpha as a crucial tumor suppressor in the endometrium, with deregulation of a PKC alpha -> PP2A/PP2A-like phosphatase signaling axis contributing to robust AKT activation and enhanced endometrial tumorigenesis.

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External Sources

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  2. DOI: 10.1016/j.celrep.2018.06.067
  3. PMID: 30021163
  4. View record in Web of Science®
  5. WOS: 000438978700013

Library Notes

  1. Fiscal Year: FY2017-2018
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