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Severe cellular stress drives apoptosis through a dual control mechanism independently of p53

For past two decades, p53 has been claimed as the primary sensor initiating apoptosis. Under severe cellular stress, p53 transcriptional activity activates BH3-only proteins such as Bim, Puma, or Noxa to nullify the inhibitory effects of anti-apoptotic proteins on pro-apoptotic proteins for mitochon...

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Autores principales: Wang, Yen-Chun, Wang, Li-Ting, Hung, Ta I, Hong, Yi-Ren, Chen, Chung-Hwan, Ho, Cheng-Jung, Wang, Chihuei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9184497/
https://www.ncbi.nlm.nih.gov/pubmed/35680784
http://dx.doi.org/10.1038/s41420-022-01078-2
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author Wang, Yen-Chun
Wang, Li-Ting
Hung, Ta I
Hong, Yi-Ren
Chen, Chung-Hwan
Ho, Cheng-Jung
Wang, Chihuei
author_facet Wang, Yen-Chun
Wang, Li-Ting
Hung, Ta I
Hong, Yi-Ren
Chen, Chung-Hwan
Ho, Cheng-Jung
Wang, Chihuei
author_sort Wang, Yen-Chun
collection PubMed
description For past two decades, p53 has been claimed as the primary sensor initiating apoptosis. Under severe cellular stress, p53 transcriptional activity activates BH3-only proteins such as Bim, Puma, or Noxa to nullify the inhibitory effects of anti-apoptotic proteins on pro-apoptotic proteins for mitochondrial outer membrane permeabilization. Cellular stress determines the expression level of p53, and the amount of p53 corresponds to the magnitude of apoptosis. However, our studies indicated that Bim and Puma are not the target genes of p53 in three cancer models, prostate cancer, glioblastoma, and osteosarcoma. Bim counteracted with Bcl-xl to activate apoptosis independently of p53 in response to doxorubicin-induced severe DNA damage in prostate cancer. Moreover, the transcriptional activity of p53 was more related to cell cycle arrest other than apoptosis for responding to DNA damage stress generated by doxorubicin in prostate cancer and glioblastoma. A proteasome inhibitor that causes protein turnover dysfunction, bortezomib, produced apoptosis in a p53-independent manner in glioblastoma and osteosarcoma. p53 in terms of both protein level and nuclear localization in combining doxorubicin with bortezomib treatment was obviously lower than when using DOX alone, inversely correlated with the magnitude of apoptosis in glioblastoma. Using a BH3-mimetic, ABT-263, to treat doxorubicin-sensitive p53-wild type and doxorubicin-resistant p53-null osteosarcoma cells demonstrated only limited apoptotic response. The combination of doxorubicin or bortezomib with ABT-263 generated a synergistic outcome of apoptosis in both p53-wild type and p53-null osteosarcoma cells. Together, this suggested that p53 might have no role in doxorubicin-induced apoptosis in prostate cancer, glioblastoma and osteosarcoma. The effects of ABT-263 in single and combination treatment of osteosarcoma or prostate cancer indicated a dual control to regulate apoptosis in response to severe cellular stress. Whether our findings only apply in these three types of cancers or extend to other cancer types remains to be explored.
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spelling pubmed-91844972022-06-11 Severe cellular stress drives apoptosis through a dual control mechanism independently of p53 Wang, Yen-Chun Wang, Li-Ting Hung, Ta I Hong, Yi-Ren Chen, Chung-Hwan Ho, Cheng-Jung Wang, Chihuei Cell Death Discov Perspective For past two decades, p53 has been claimed as the primary sensor initiating apoptosis. Under severe cellular stress, p53 transcriptional activity activates BH3-only proteins such as Bim, Puma, or Noxa to nullify the inhibitory effects of anti-apoptotic proteins on pro-apoptotic proteins for mitochondrial outer membrane permeabilization. Cellular stress determines the expression level of p53, and the amount of p53 corresponds to the magnitude of apoptosis. However, our studies indicated that Bim and Puma are not the target genes of p53 in three cancer models, prostate cancer, glioblastoma, and osteosarcoma. Bim counteracted with Bcl-xl to activate apoptosis independently of p53 in response to doxorubicin-induced severe DNA damage in prostate cancer. Moreover, the transcriptional activity of p53 was more related to cell cycle arrest other than apoptosis for responding to DNA damage stress generated by doxorubicin in prostate cancer and glioblastoma. A proteasome inhibitor that causes protein turnover dysfunction, bortezomib, produced apoptosis in a p53-independent manner in glioblastoma and osteosarcoma. p53 in terms of both protein level and nuclear localization in combining doxorubicin with bortezomib treatment was obviously lower than when using DOX alone, inversely correlated with the magnitude of apoptosis in glioblastoma. Using a BH3-mimetic, ABT-263, to treat doxorubicin-sensitive p53-wild type and doxorubicin-resistant p53-null osteosarcoma cells demonstrated only limited apoptotic response. The combination of doxorubicin or bortezomib with ABT-263 generated a synergistic outcome of apoptosis in both p53-wild type and p53-null osteosarcoma cells. Together, this suggested that p53 might have no role in doxorubicin-induced apoptosis in prostate cancer, glioblastoma and osteosarcoma. The effects of ABT-263 in single and combination treatment of osteosarcoma or prostate cancer indicated a dual control to regulate apoptosis in response to severe cellular stress. Whether our findings only apply in these three types of cancers or extend to other cancer types remains to be explored. Nature Publishing Group UK 2022-06-09 /pmc/articles/PMC9184497/ /pubmed/35680784 http://dx.doi.org/10.1038/s41420-022-01078-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Perspective
Wang, Yen-Chun
Wang, Li-Ting
Hung, Ta I
Hong, Yi-Ren
Chen, Chung-Hwan
Ho, Cheng-Jung
Wang, Chihuei
Severe cellular stress drives apoptosis through a dual control mechanism independently of p53
title Severe cellular stress drives apoptosis through a dual control mechanism independently of p53
title_full Severe cellular stress drives apoptosis through a dual control mechanism independently of p53
title_fullStr Severe cellular stress drives apoptosis through a dual control mechanism independently of p53
title_full_unstemmed Severe cellular stress drives apoptosis through a dual control mechanism independently of p53
title_short Severe cellular stress drives apoptosis through a dual control mechanism independently of p53
title_sort severe cellular stress drives apoptosis through a dual control mechanism independently of p53
topic Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9184497/
https://www.ncbi.nlm.nih.gov/pubmed/35680784
http://dx.doi.org/10.1038/s41420-022-01078-2
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