Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.

Heme is an essential cofactor for enzymes of the electron transport chain (ETC) and ATP synthesis in mitochondrial oxidative phosphorylation (OXPHOS). Heme also binds to and destabilizes Bach1, a transcription regulator that controls expression of several groups of genes important for glycolysis, ET...

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Autores principales:	Pritpal Kaur, Shreya Nagar, Madhura Bhagwat, Mohammad Uddin, Yan Zhu, Ivana Vancurova, Ales Vancura
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/020bef64cbbe4de08832db9cc3b7ff18
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spelling	oai:doaj.org-article:020bef64cbbe4de08832db9cc3b7ff182021-12-02T20:16:16ZActivated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.1932-620310.1371/journal.pone.0260400https://doaj.org/article/020bef64cbbe4de08832db9cc3b7ff182021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0260400https://doaj.org/toc/1932-6203Heme is an essential cofactor for enzymes of the electron transport chain (ETC) and ATP synthesis in mitochondrial oxidative phosphorylation (OXPHOS). Heme also binds to and destabilizes Bach1, a transcription regulator that controls expression of several groups of genes important for glycolysis, ETC, and metastasis of cancer cells. Heme synthesis can thus affect pathways through which cells generate energy and precursors for anabolism. In addition, increased heme synthesis may trigger oxidative stress. Since many cancers are characterized by a high glycolytic rate regardless of oxygen availability, targeting glycolysis, ETC, and OXPHOS have emerged as a potential therapeutic strategy. Here, we report that enhancing heme synthesis through exogenous supplementation of heme precursor 5-aminolevulinic acid (ALA) suppresses oxidative metabolism as well as glycolysis and significantly reduces proliferation of both ovarian and breast cancer cells. ALA supplementation also destabilizes Bach1 and inhibits migration of both cell types. Our data indicate that the underlying mechanisms differ in ovarian and breast cancer cells, but involve destabilization of Bach1, AMPK activation, and induction of oxidative stress. In addition, there appears to be an inverse correlation between the activity of oxidative metabolism and ALA sensitivity. Promoting heme synthesis by ALA supplementation may thus represent a promising new anti-cancer strategy, particularly in cancers that are sensitive to altered redox signaling, or in combination with strategies that target the antioxidant systems or metabolic weaknesses of cancer cells.Pritpal KaurShreya NagarMadhura BhagwatMohammad UddinYan ZhuIvana VancurovaAles VancuraPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11, p e0260400 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pritpal Kaur Shreya Nagar Madhura Bhagwat Mohammad Uddin Yan Zhu Ivana Vancurova Ales Vancura Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.
description	Heme is an essential cofactor for enzymes of the electron transport chain (ETC) and ATP synthesis in mitochondrial oxidative phosphorylation (OXPHOS). Heme also binds to and destabilizes Bach1, a transcription regulator that controls expression of several groups of genes important for glycolysis, ETC, and metastasis of cancer cells. Heme synthesis can thus affect pathways through which cells generate energy and precursors for anabolism. In addition, increased heme synthesis may trigger oxidative stress. Since many cancers are characterized by a high glycolytic rate regardless of oxygen availability, targeting glycolysis, ETC, and OXPHOS have emerged as a potential therapeutic strategy. Here, we report that enhancing heme synthesis through exogenous supplementation of heme precursor 5-aminolevulinic acid (ALA) suppresses oxidative metabolism as well as glycolysis and significantly reduces proliferation of both ovarian and breast cancer cells. ALA supplementation also destabilizes Bach1 and inhibits migration of both cell types. Our data indicate that the underlying mechanisms differ in ovarian and breast cancer cells, but involve destabilization of Bach1, AMPK activation, and induction of oxidative stress. In addition, there appears to be an inverse correlation between the activity of oxidative metabolism and ALA sensitivity. Promoting heme synthesis by ALA supplementation may thus represent a promising new anti-cancer strategy, particularly in cancers that are sensitive to altered redox signaling, or in combination with strategies that target the antioxidant systems or metabolic weaknesses of cancer cells.
format	article
author	Pritpal Kaur Shreya Nagar Madhura Bhagwat Mohammad Uddin Yan Zhu Ivana Vancurova Ales Vancura
author_facet	Pritpal Kaur Shreya Nagar Madhura Bhagwat Mohammad Uddin Yan Zhu Ivana Vancurova Ales Vancura
author_sort	Pritpal Kaur
title	Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.
title_short	Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.
title_full	Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.
title_fullStr	Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.
title_full_unstemmed	Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.
title_sort	activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/020bef64cbbe4de08832db9cc3b7ff18
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Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.

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