Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation

Abstract The prevalence and dire implications of mutations in the tumour suppressor, p53, highlight its appeal as a chemotherapeutic target. We recently showed that impairing cellular antioxidant systems via inhibition of SLC7A11, a component of the system xc − cystine-glutamate antiporter, enhances...

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Autores principales:	Julia V. Milne, Bonnie Z. Zhang, Kenji M. Fujihara, Swati Dawar, Wayne A. Phillips, Nicholas J. Clemons
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ba9b4fb88cd4428c8a2cf11039b060f4
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spelling	oai:doaj.org-article:ba9b4fb88cd4428c8a2cf11039b060f42021-12-02T11:37:26ZTransketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation10.1038/s41598-021-83979-32045-2322https://doaj.org/article/ba9b4fb88cd4428c8a2cf11039b060f42021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83979-3https://doaj.org/toc/2045-2322Abstract The prevalence and dire implications of mutations in the tumour suppressor, p53, highlight its appeal as a chemotherapeutic target. We recently showed that impairing cellular antioxidant systems via inhibition of SLC7A11, a component of the system xc − cystine-glutamate antiporter, enhances sensitivity to mutant-p53 targeted therapy, APR-246. We investigated whether this synergy extends to other genes, such as those encoding enzymes of the pentose phosphate pathway (PPP). TKT, one of the major enzymes of the PPP, is allegedly regulated by NRF2, which is in turn impaired by accumulated mutant-p53 protein. Therefore, we investigated the relationship between mutant-p53, TKT and sensitivity to APR-246. We found that mutant-p53 does not alter expression of TKT, nor is TKT modulated directly by NRF2, suggesting a more complex mechanism at play. Furthermore, we found that in p53null cells, knockdown of TKT increased sensitivity to APR-246, whilst TKT overexpression conferred resistance to the drug. However, neither permutation elicited any effect on cells overexpressing mutant-p53 protein, despite mediating oxidative stress levels in a similar fashion to that in p53-null cells. In sum, this study has unveiled TKT expression as a determinant for sensitivity to APR-246 in p53-null cells.Julia V. MilneBonnie Z. ZhangKenji M. FujiharaSwati DawarWayne A. PhillipsNicholas J. ClemonsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Julia V. Milne Bonnie Z. Zhang Kenji M. Fujihara Swati Dawar Wayne A. Phillips Nicholas J. Clemons Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation
description	Abstract The prevalence and dire implications of mutations in the tumour suppressor, p53, highlight its appeal as a chemotherapeutic target. We recently showed that impairing cellular antioxidant systems via inhibition of SLC7A11, a component of the system xc − cystine-glutamate antiporter, enhances sensitivity to mutant-p53 targeted therapy, APR-246. We investigated whether this synergy extends to other genes, such as those encoding enzymes of the pentose phosphate pathway (PPP). TKT, one of the major enzymes of the PPP, is allegedly regulated by NRF2, which is in turn impaired by accumulated mutant-p53 protein. Therefore, we investigated the relationship between mutant-p53, TKT and sensitivity to APR-246. We found that mutant-p53 does not alter expression of TKT, nor is TKT modulated directly by NRF2, suggesting a more complex mechanism at play. Furthermore, we found that in p53null cells, knockdown of TKT increased sensitivity to APR-246, whilst TKT overexpression conferred resistance to the drug. However, neither permutation elicited any effect on cells overexpressing mutant-p53 protein, despite mediating oxidative stress levels in a similar fashion to that in p53-null cells. In sum, this study has unveiled TKT expression as a determinant for sensitivity to APR-246 in p53-null cells.
format	article
author	Julia V. Milne Bonnie Z. Zhang Kenji M. Fujihara Swati Dawar Wayne A. Phillips Nicholas J. Clemons
author_facet	Julia V. Milne Bonnie Z. Zhang Kenji M. Fujihara Swati Dawar Wayne A. Phillips Nicholas J. Clemons
author_sort	Julia V. Milne
title	Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation
title_short	Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation
title_full	Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation
title_fullStr	Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation
title_full_unstemmed	Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation
title_sort	transketolase regulates sensitivity to apr-246 in p53-null cells independently of oxidative stress modulation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ba9b4fb88cd4428c8a2cf11039b060f4
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Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation

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