In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 11 ( 2021-11-22), p. e0260400-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0260400
DOI:
10.1371/journal.pone.0260400.g001
DOI:
10.1371/journal.pone.0260400.g002
DOI:
10.1371/journal.pone.0260400.g003
DOI:
10.1371/journal.pone.0260400.g004
DOI:
10.1371/journal.pone.0260400.g005
DOI:
10.1371/journal.pone.0260400.g006
DOI:
10.1371/journal.pone.0260400.g007
DOI:
10.1371/journal.pone.0260400.g008
DOI:
10.1371/journal.pone.0260400.t001
DOI:
10.1371/journal.pone.0260400.s001
DOI:
10.1371/journal.pone.0260400.s002
DOI:
10.1371/journal.pone.0260400.r001
DOI:
10.1371/journal.pone.0260400.r002
DOI:
10.1371/journal.pone.0260400.r003
DOI:
10.1371/journal.pone.0260400.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
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