Cargando…

Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction

Cancer cells depend on glutamine to sustain their increased proliferation and manage oxidative stress, yet glutamine is often depleted at tumor sites due to excessive cellular consumption and poor vascularization. We have previously reported that p53 protein, while a well-known tumor suppressor, can...

Descripción completa

Detalles Bibliográficos
Autores principales: Tran, Thai Q., Lowman, Xazmin H., Reid, Michael A., Mendez-Dorantes, Carlos, Pan, Min, Yang, Ying, Kong, Mei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383530/
https://www.ncbi.nlm.nih.gov/pubmed/27721412
http://dx.doi.org/10.1038/onc.2016.360
_version_ 1782520293943672832
author Tran, Thai Q.
Lowman, Xazmin H.
Reid, Michael A.
Mendez-Dorantes, Carlos
Pan, Min
Yang, Ying
Kong, Mei
author_facet Tran, Thai Q.
Lowman, Xazmin H.
Reid, Michael A.
Mendez-Dorantes, Carlos
Pan, Min
Yang, Ying
Kong, Mei
author_sort Tran, Thai Q.
collection PubMed
description Cancer cells depend on glutamine to sustain their increased proliferation and manage oxidative stress, yet glutamine is often depleted at tumor sites due to excessive cellular consumption and poor vascularization. We have previously reported that p53 protein, while a well-known tumor suppressor, can contribute to cancer cell survival and adaptation to low glutamine conditions. However, the TP53 gene is frequently mutated in tumors, and the role of mutant p53 (mutp53) in response to metabolic stress remains unclear. Here, we demonstrate that tumor-associated mutp53 promotes cancer cell survival upon glutamine deprivation both in vitro and in vivo. Interestingly, cancer cells expressing mutp53 proteins are more resistant to glutamine deprivation than cells with wild type p53 (wtp53). Depletion of endogenous mutp53 protein in human lymphoma cells leads to cell sensitivity to glutamine withdrawal, while expression of mutp53 in p53 null cells results in resistance to glutamine deprivation. Furthermore, we found that mutp53 proteins hyper-transactivate p53 target gene CDKN1A upon glutamine deprivation, thus triggering cell cycle arrest and promoting cell survival. Together, our results reveal an unidentified mechanism by which mutp53 confers oncogenic functions by promoting cancer cell adaptation to metabolic stresses.
format Online
Article
Text
id pubmed-5383530
institution National Center for Biotechnology Information
language English
publishDate 2016
record_format MEDLINE/PubMed
spelling pubmed-53835302017-04-10 Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction Tran, Thai Q. Lowman, Xazmin H. Reid, Michael A. Mendez-Dorantes, Carlos Pan, Min Yang, Ying Kong, Mei Oncogene Article Cancer cells depend on glutamine to sustain their increased proliferation and manage oxidative stress, yet glutamine is often depleted at tumor sites due to excessive cellular consumption and poor vascularization. We have previously reported that p53 protein, while a well-known tumor suppressor, can contribute to cancer cell survival and adaptation to low glutamine conditions. However, the TP53 gene is frequently mutated in tumors, and the role of mutant p53 (mutp53) in response to metabolic stress remains unclear. Here, we demonstrate that tumor-associated mutp53 promotes cancer cell survival upon glutamine deprivation both in vitro and in vivo. Interestingly, cancer cells expressing mutp53 proteins are more resistant to glutamine deprivation than cells with wild type p53 (wtp53). Depletion of endogenous mutp53 protein in human lymphoma cells leads to cell sensitivity to glutamine withdrawal, while expression of mutp53 in p53 null cells results in resistance to glutamine deprivation. Furthermore, we found that mutp53 proteins hyper-transactivate p53 target gene CDKN1A upon glutamine deprivation, thus triggering cell cycle arrest and promoting cell survival. Together, our results reveal an unidentified mechanism by which mutp53 confers oncogenic functions by promoting cancer cell adaptation to metabolic stresses. 2016-10-10 2017-04-06 /pmc/articles/PMC5383530/ /pubmed/27721412 http://dx.doi.org/10.1038/onc.2016.360 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Tran, Thai Q.
Lowman, Xazmin H.
Reid, Michael A.
Mendez-Dorantes, Carlos
Pan, Min
Yang, Ying
Kong, Mei
Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction
title Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction
title_full Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction
title_fullStr Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction
title_full_unstemmed Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction
title_short Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction
title_sort tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383530/
https://www.ncbi.nlm.nih.gov/pubmed/27721412
http://dx.doi.org/10.1038/onc.2016.360
work_keys_str_mv AT tranthaiq tumorassociatedmutantp53promotescancercellsurvivaluponglutaminedeprivationthroughp21induction
AT lowmanxazminh tumorassociatedmutantp53promotescancercellsurvivaluponglutaminedeprivationthroughp21induction
AT reidmichaela tumorassociatedmutantp53promotescancercellsurvivaluponglutaminedeprivationthroughp21induction
AT mendezdorantescarlos tumorassociatedmutantp53promotescancercellsurvivaluponglutaminedeprivationthroughp21induction
AT panmin tumorassociatedmutantp53promotescancercellsurvivaluponglutaminedeprivationthroughp21induction
AT yangying tumorassociatedmutantp53promotescancercellsurvivaluponglutaminedeprivationthroughp21induction
AT kongmei tumorassociatedmutantp53promotescancercellsurvivaluponglutaminedeprivationthroughp21induction