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Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells

We have extended our analyses of HDAC inhibitor biology in sarcoma. The multi-kinase inhibitor axitinib interacted with multiple HDAC inhibitors to kill sarcoma cells. Axitinib and HDAC inhibitors interacted in a greater than additive fashion to inactivate AKT, mTORC1 and mTORC2, and to increase Rap...

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Autores principales: Roberts, Jane L., Booth, Laurence, Poklepovic, Andrew, Dent, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483767/
https://www.ncbi.nlm.nih.gov/pubmed/34604061
http://dx.doi.org/10.3389/fonc.2021.723966
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author Roberts, Jane L.
Booth, Laurence
Poklepovic, Andrew
Dent, Paul
author_facet Roberts, Jane L.
Booth, Laurence
Poklepovic, Andrew
Dent, Paul
author_sort Roberts, Jane L.
collection PubMed
description We have extended our analyses of HDAC inhibitor biology in sarcoma. The multi-kinase inhibitor axitinib interacted with multiple HDAC inhibitors to kill sarcoma cells. Axitinib and HDAC inhibitors interacted in a greater than additive fashion to inactivate AKT, mTORC1 and mTORC2, and to increase Raptor S722/S792 phosphorylation. Individually, all drugs increased phosphorylation of ATM S1981, AMPKα T172, ULK1 S317 and ATG13 S318 and reduced ULK1 S757 phosphorylation; this correlated with enhanced autophagic flux. Increased phosphorylation of ULK1 S317 and of Raptor S722/S792 required ATM-AMPK signaling. ULK1 S757 is a recognized site for mTORC1 and knock down of either ATM or AMPKα reduced the drug-induced dephosphorylation of this site. Combined exposure of cells to axitinib and an HDAC inhibitor significantly reduced the expression of HDAC1, HDAC2, HDAC3, HDAC4, HDAC6 and HDAC7. No response was observed for HDACs 10 and 11. Knock down of ULK1, Beclin1 or ATG5 prevented the decline in HDAC expression, as did expression of a constitutively active mTOR protein. Axitinib combined with HDAC inhibitors enhanced expression of Class I MHCA and reduced expression of PD-L1 which was recapitulated via knock down studies, particularly of HDACs 1 and 3. In vivo, axitinib and the HDAC inhibitor entinostat interacted to significantly reduce tumor growth. Collectively our findings support the exploration of axitinib and HDAC inhibitors being developed as a novel sarcoma therapy.
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spelling pubmed-84837672021-10-01 Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells Roberts, Jane L. Booth, Laurence Poklepovic, Andrew Dent, Paul Front Oncol Oncology We have extended our analyses of HDAC inhibitor biology in sarcoma. The multi-kinase inhibitor axitinib interacted with multiple HDAC inhibitors to kill sarcoma cells. Axitinib and HDAC inhibitors interacted in a greater than additive fashion to inactivate AKT, mTORC1 and mTORC2, and to increase Raptor S722/S792 phosphorylation. Individually, all drugs increased phosphorylation of ATM S1981, AMPKα T172, ULK1 S317 and ATG13 S318 and reduced ULK1 S757 phosphorylation; this correlated with enhanced autophagic flux. Increased phosphorylation of ULK1 S317 and of Raptor S722/S792 required ATM-AMPK signaling. ULK1 S757 is a recognized site for mTORC1 and knock down of either ATM or AMPKα reduced the drug-induced dephosphorylation of this site. Combined exposure of cells to axitinib and an HDAC inhibitor significantly reduced the expression of HDAC1, HDAC2, HDAC3, HDAC4, HDAC6 and HDAC7. No response was observed for HDACs 10 and 11. Knock down of ULK1, Beclin1 or ATG5 prevented the decline in HDAC expression, as did expression of a constitutively active mTOR protein. Axitinib combined with HDAC inhibitors enhanced expression of Class I MHCA and reduced expression of PD-L1 which was recapitulated via knock down studies, particularly of HDACs 1 and 3. In vivo, axitinib and the HDAC inhibitor entinostat interacted to significantly reduce tumor growth. Collectively our findings support the exploration of axitinib and HDAC inhibitors being developed as a novel sarcoma therapy. Frontiers Media S.A. 2021-09-16 /pmc/articles/PMC8483767/ /pubmed/34604061 http://dx.doi.org/10.3389/fonc.2021.723966 Text en Copyright © 2021 Roberts, Booth, Poklepovic and Dent https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Roberts, Jane L.
Booth, Laurence
Poklepovic, Andrew
Dent, Paul
Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells
title Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells
title_full Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells
title_fullStr Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells
title_full_unstemmed Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells
title_short Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells
title_sort axitinib and hdac inhibitors interact to kill sarcoma cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483767/
https://www.ncbi.nlm.nih.gov/pubmed/34604061
http://dx.doi.org/10.3389/fonc.2021.723966
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