Ascorbate induces apoptosis in melanoma cells by suppressing Clusterin expression

Abstract Pharmacological levels of ascorbate have long been suggested as a potential treatment of cancer. However, we observed that EC50 of ascorbate was at a similar level for cultured healthy melanocytes and melanoma cells, suggesting a limit of pharmacological ascorbate in treating cancer. Loss o...

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Autores principales:	Sushmita Mustafi, David W. Sant, Zhao-Jun Liu, Gaofeng Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c22ec85d07c34fba99d8b4a8dc80b97d
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spelling	oai:doaj.org-article:c22ec85d07c34fba99d8b4a8dc80b97d2021-12-02T12:32:06ZAscorbate induces apoptosis in melanoma cells by suppressing Clusterin expression10.1038/s41598-017-03893-52045-2322https://doaj.org/article/c22ec85d07c34fba99d8b4a8dc80b97d2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03893-5https://doaj.org/toc/2045-2322Abstract Pharmacological levels of ascorbate have long been suggested as a potential treatment of cancer. However, we observed that EC50 of ascorbate was at a similar level for cultured healthy melanocytes and melanoma cells, suggesting a limit of pharmacological ascorbate in treating cancer. Loss of 5-hydroxymethylcytosine (5 hmC) is an epigenetic hallmark of cancer and ascorbate promotes 5 hmC generation by serving as a cofactor for TET methylcytosine dioxygenases. Our previous work demonstrated that ascorbate treatment at physiological level (100 μM) increased 5 hmC content in melanoma cells toward the level of healthy melanocytes. Here we show that 100 µM of ascorbate induced apoptosis in A2058 melanoma cells. RNA-seq analysis revealed that expression of the Clusterin (CLU) gene, which is related to apoptosis, was downregulated by ascorbate. The suppression of CLU was verified at transcript level in different melanoma cell lines, and at protein level in A2058 cells. The anti-apoptotic cytoplasmic CLU was decreased, while the pro-apoptotic nuclear CLU was largely maintained, after ascorbate treatment. These changes in CLU subcellular localization were also associated with Bax and caspases activation, Bcl-xL sequestration, and cytochrome c release. Taken together, this study establishes an impending therapeutic role of physiological ascorbate to potentiate apoptosis in melanoma.Sushmita MustafiDavid W. SantZhao-Jun LiuGaofeng WangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sushmita Mustafi David W. Sant Zhao-Jun Liu Gaofeng Wang Ascorbate induces apoptosis in melanoma cells by suppressing Clusterin expression
description	Abstract Pharmacological levels of ascorbate have long been suggested as a potential treatment of cancer. However, we observed that EC50 of ascorbate was at a similar level for cultured healthy melanocytes and melanoma cells, suggesting a limit of pharmacological ascorbate in treating cancer. Loss of 5-hydroxymethylcytosine (5 hmC) is an epigenetic hallmark of cancer and ascorbate promotes 5 hmC generation by serving as a cofactor for TET methylcytosine dioxygenases. Our previous work demonstrated that ascorbate treatment at physiological level (100 μM) increased 5 hmC content in melanoma cells toward the level of healthy melanocytes. Here we show that 100 µM of ascorbate induced apoptosis in A2058 melanoma cells. RNA-seq analysis revealed that expression of the Clusterin (CLU) gene, which is related to apoptosis, was downregulated by ascorbate. The suppression of CLU was verified at transcript level in different melanoma cell lines, and at protein level in A2058 cells. The anti-apoptotic cytoplasmic CLU was decreased, while the pro-apoptotic nuclear CLU was largely maintained, after ascorbate treatment. These changes in CLU subcellular localization were also associated with Bax and caspases activation, Bcl-xL sequestration, and cytochrome c release. Taken together, this study establishes an impending therapeutic role of physiological ascorbate to potentiate apoptosis in melanoma.
format	article
author	Sushmita Mustafi David W. Sant Zhao-Jun Liu Gaofeng Wang
author_facet	Sushmita Mustafi David W. Sant Zhao-Jun Liu Gaofeng Wang
author_sort	Sushmita Mustafi
title	Ascorbate induces apoptosis in melanoma cells by suppressing Clusterin expression
title_short	Ascorbate induces apoptosis in melanoma cells by suppressing Clusterin expression
title_full	Ascorbate induces apoptosis in melanoma cells by suppressing Clusterin expression
title_fullStr	Ascorbate induces apoptosis in melanoma cells by suppressing Clusterin expression
title_full_unstemmed	Ascorbate induces apoptosis in melanoma cells by suppressing Clusterin expression
title_sort	ascorbate induces apoptosis in melanoma cells by suppressing clusterin expression
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c22ec85d07c34fba99d8b4a8dc80b97d
work_keys_str_mv	AT sushmitamustafi ascorbateinducesapoptosisinmelanomacellsbysuppressingclusterinexpression AT davidwsant ascorbateinducesapoptosisinmelanomacellsbysuppressingclusterinexpression AT zhaojunliu ascorbateinducesapoptosisinmelanomacellsbysuppressingclusterinexpression AT gaofengwang ascorbateinducesapoptosisinmelanomacellsbysuppressingclusterinexpression
_version_	1718394183414185984

Ascorbate induces apoptosis in melanoma cells by suppressing Clusterin expression

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