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

Autor:	Hsu AH; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Lum MA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Shim KS; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA., Frederick PJ; Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Morrison CD; Department of Pathology and Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Chen B; Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA., Lele SM; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Sheinin YM; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Daikoku T; Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Dey SK; Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Leone G; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA., Black AR; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Black JD; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: jennifer.black@unmc.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2018 Jul 17; Vol. 24 (3), pp. 655-669.
DOI:	10.1016/j.celrep.2018.06.067
Abstrakt:	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. (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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