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BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis

Journal article
Authors Clotilde Wiel
Kristell Le Gal
M. X. Ibrahim
C. A. Jahangir
M. Kashif
H. D. Yao
Dorian V. Ziegler
X. F. Xu
Tanushree Ghosh
Tanmoy Mondal
Chandrasekhar Kanduri
Per Lindahl
Volkan I. Sayin
Martin O. Bergo
Published in Cell
Volume 178
Issue 2
Pages 330-+
ISSN 0092-8674
Publication year 2019
Published at Wallenberg Laboratory
Sahlgrenska Cancer Center
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 330-+
Language en
Links dx.doi.org/10.1016/j.cell.2019.06.0...
Keywords gene-expression, mouse models, heme, ros, mechanisms, glycolysis, pathway, progression, activation, induction, Biochemistry & Molecular Biology, Cell Biology
Subject categories Cancer and Oncology

Abstract

For tumors to progress efficiently, cancer cells must overcome barriers of oxidative stress. Although dietary antioxidant supplementation or activation of endogenous antioxidants by NRF2 reduces oxidative stress and promotes early lung tumor progression, little is known about its effect on lung cancer metastasis. Here, we show that long-term supplementation with the antioxidants N-acetylcysteine and vitamin E promotes KRAS-driven lung cancer metastasis. The antioxidants stimulate metastasis by reducing levels of free heme and stabilizing the transcription factor BACH1. BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. Targeting BACH1 normalized glycolysis and prevented antioxidant-induced metastasis, while increasing endogenous BACH1 expression stimulated glycolysis and promoted metastasis, also in the absence of antioxidants. We conclude that BACH1 stimulates glycolysis-dependent lung cancer metastasis and that BACH1 is activated under conditions of reduced oxidative stress.

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