2. Academic Validation
  3. BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis

BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis

  • Cell. 2019 Jul 11;178(2):330-345.e22. doi: 10.1016/j.cell.2019.06.005.
Clotilde Wiel 1,  Kristell Le Gal 2,  Mohamed X Ibrahim 3,  Chowdhury Arif Jahangir 4,  Muhammad Kashif 4,  Haidong Yao 4,  Dorian V Ziegler 3,  Xiufeng Xu 4,  Tanushree Ghosh 5,  Tanmoy Mondal 5,  Chandrasekhar Kanduri 5,  Per Lindahl 6,  Volkan I Sayin 7,  Martin O Bergo 8
Affiliations

Affiliations

  • 1 Department of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden; Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden.
  • 2 Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, 405 30 Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden.
  • 3 Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden.
  • 4 Department of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden.
  • 5 Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, 405 30 Gothenburg, Sweden.
  • 6 The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden.
  • 7 Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, 405 30 Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden. Electronic address: volkan.sayin@gu.se.
  • 8 Department of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden; Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden. Electronic address: martin.bergo@ki.se.
PMID: 31257027 DOI: 10.1016/j.cell.2019.06.005
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.

Keywords

BACH1; KRAS; antioxidants; heme; lung cancer metastasis; mouse models; oxidative stress.

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