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

Cell Reports
Alice H HsuJennifer D Black

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.

Citations

Jan 28, 2021·The Biochemical Journal·Hannah Tovell, Alexandra C Newton
Feb 14, 2021·BMC Cancer·Hui ChenQingping Jiang
Oct 6, 2020·Advances in Biological Regulation·Nilufar RahimovaMarcelo G Kazanietz
Dec 12, 2020·Advances in Biological Regulation·Adrian R Black, Jennifer D Black
Apr 17, 2021·Trends in Endocrinology and Metabolism : TEM·Devanshi Mishra, Chinmoy Sankar Dey
Jun 3, 2021·Medical Sciences : Open Access Journal·Christina BorchersRavi P Sahu
May 2, 2021·Molecular Cancer Research : MCR·Seamus E Degan, Irwin H Gelman

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Methods Mentioned

BETA
protein array
laser capture microdissection
genotyping
transfection
Immunoprecipitation

Software Mentioned

GraphPad Prism
Adobe Photoshop CC
SAS
Excel

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