Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer

Zuen Ren, Huizhi Liang, Phillip M. Galbo, Malindrie Dharmaratne, Ameya S. Kulkarni, Atefeh Taherian Fard, Marie Louise Aoun, Nuria Martinez-Lopez, Kimita Suyama, Outhiriaradjou Benard, Wei Zheng, Yang Liu, Joseph Albanese, Deyou Zheng, Jessica C. Mar, Rajat Singh, Michael B. Prystowsky, Larry Norton, Rachel B. Hazan

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.

Original languageEnglish (US)
Article numbere2107266119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number8
DOIs
StatePublished - Feb 22 2022

Keywords

  • Breast cancer
  • HIF1α
  • ROS signaling
  • glutathione peroxidase 2
  • metabolism

ASJC Scopus subject areas

  • General

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