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P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway

Positive transcription elongation factor b (P-TEFb) is the crucial player in RNA polymerase II (Pol II) pause release that has emerged as a promising target in cancer. Because single-agent therapy may fail to deliver durable clinical response, targeting of P-TEFb shall benefit when deployed as a com...

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Autores principales: Wang, Zhijia, Mačáková, Monika, Bugai, Andrii, Kuznetsov, Sergey G, Hassinen, Antti, Lenasi, Tina, Potdar, Swapnil, Friedel, Caroline C, Barborič, Matjaž
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9976905/
https://www.ncbi.nlm.nih.gov/pubmed/36727434
http://dx.doi.org/10.1093/nar/gkad001
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author Wang, Zhijia
Mačáková, Monika
Bugai, Andrii
Kuznetsov, Sergey G
Hassinen, Antti
Lenasi, Tina
Potdar, Swapnil
Friedel, Caroline C
Barborič, Matjaž
author_facet Wang, Zhijia
Mačáková, Monika
Bugai, Andrii
Kuznetsov, Sergey G
Hassinen, Antti
Lenasi, Tina
Potdar, Swapnil
Friedel, Caroline C
Barborič, Matjaž
author_sort Wang, Zhijia
collection PubMed
description Positive transcription elongation factor b (P-TEFb) is the crucial player in RNA polymerase II (Pol II) pause release that has emerged as a promising target in cancer. Because single-agent therapy may fail to deliver durable clinical response, targeting of P-TEFb shall benefit when deployed as a combination therapy. We screened a comprehensive oncology library and identified clinically relevant antimetabolites and Mouse double minute 2 homolog (MDM2) inhibitors as top compounds eliciting p53-dependent death of colorectal cancer cells in synergy with selective inhibitors of P-TEFb. While the targeting of P-TEFb augments apoptosis by anti-metabolite 5-fluorouracil, it switches the fate of cancer cells by the non-genotoxic MDM2 inhibitor Nutlin-3a from cell-cycle arrest to apoptosis. Mechanistically, the fate switching is enabled by the induction of p53-dependent pro-apoptotic genes and repression of P-TEFb-dependent pro-survival genes of the PI3K-AKT signaling cascade, which stimulates caspase 9 and intrinsic apoptosis pathway in BAX/BAK-dependent manner. Finally, combination treatments trigger apoptosis of cancer cell spheroids. Together, co-targeting of P-TEFb and suppressors of intrinsic apoptosis could become a viable strategy to eliminate cancer cells.
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spelling pubmed-99769052023-03-02 P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway Wang, Zhijia Mačáková, Monika Bugai, Andrii Kuznetsov, Sergey G Hassinen, Antti Lenasi, Tina Potdar, Swapnil Friedel, Caroline C Barborič, Matjaž Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Positive transcription elongation factor b (P-TEFb) is the crucial player in RNA polymerase II (Pol II) pause release that has emerged as a promising target in cancer. Because single-agent therapy may fail to deliver durable clinical response, targeting of P-TEFb shall benefit when deployed as a combination therapy. We screened a comprehensive oncology library and identified clinically relevant antimetabolites and Mouse double minute 2 homolog (MDM2) inhibitors as top compounds eliciting p53-dependent death of colorectal cancer cells in synergy with selective inhibitors of P-TEFb. While the targeting of P-TEFb augments apoptosis by anti-metabolite 5-fluorouracil, it switches the fate of cancer cells by the non-genotoxic MDM2 inhibitor Nutlin-3a from cell-cycle arrest to apoptosis. Mechanistically, the fate switching is enabled by the induction of p53-dependent pro-apoptotic genes and repression of P-TEFb-dependent pro-survival genes of the PI3K-AKT signaling cascade, which stimulates caspase 9 and intrinsic apoptosis pathway in BAX/BAK-dependent manner. Finally, combination treatments trigger apoptosis of cancer cell spheroids. Together, co-targeting of P-TEFb and suppressors of intrinsic apoptosis could become a viable strategy to eliminate cancer cells. Oxford University Press 2023-02-02 /pmc/articles/PMC9976905/ /pubmed/36727434 http://dx.doi.org/10.1093/nar/gkad001 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Gene regulation, Chromatin and Epigenetics
Wang, Zhijia
Mačáková, Monika
Bugai, Andrii
Kuznetsov, Sergey G
Hassinen, Antti
Lenasi, Tina
Potdar, Swapnil
Friedel, Caroline C
Barborič, Matjaž
P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway
title P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway
title_full P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway
title_fullStr P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway
title_full_unstemmed P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway
title_short P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway
title_sort p-tefb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9976905/
https://www.ncbi.nlm.nih.gov/pubmed/36727434
http://dx.doi.org/10.1093/nar/gkad001
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