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

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? acts as a tumor suppressor in PI3K/AKT-driven endometrial cancer. Transcriptional suppression of PKC? is observed in human endometrial tumors in association with aggressive disease and poor prognosis. In murine models, loss of PKC? is rate limiting for endometrial tumor initiation. PKC? 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? as a crucial tumor suppressor in the endometrium, with deregulation of a PKC??PP2A/PP2A-like phosphatase signaling axis contributing to robust AKT activation and enhanced endometrial tumorigenesis.

SUBMITTER: Hsu AH 

PROVIDER: S-EPMC6118133 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature