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Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium
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 suppressi...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118133/ https://www.ncbi.nlm.nih.gov/pubmed/30021163 http://dx.doi.org/10.1016/j.celrep.2018.06.067 |
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author | Hsu, Alice H. 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. |
author_facet | Hsu, Alice H. 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. |
author_sort | Hsu, Alice H. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6118133 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
spelling | pubmed-61181332018-08-31 Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium Hsu, Alice H. 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. Cell Rep Article 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. 2018-07-17 /pmc/articles/PMC6118133/ /pubmed/30021163 http://dx.doi.org/10.1016/j.celrep.2018.06.067 Text en Open Access This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Hsu, Alice H. 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. Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium |
title | Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium |
title_full | Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium |
title_fullStr | Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium |
title_full_unstemmed | Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium |
title_short | Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium |
title_sort | crosstalk between pkcα and pi3k/akt signaling is tumor suppressive in the endometrium |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118133/ https://www.ncbi.nlm.nih.gov/pubmed/30021163 http://dx.doi.org/10.1016/j.celrep.2018.06.067 |
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