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

Ren, Zuen, Liang, Huizhi, Galbo, Phillip M, Dharmaratne, Malindrie, Kulkarni, Ameya S, Fard, Atefeh Taherian, Aoun, Marie Louise, Martinez-Lopez, Nuria, Suyama, Kimita, Benard, Outhiriaradjou, Zheng, Wei, Liu, Yang, Albanese, Joseph, Zheng, Deyou, Mar, Jessica C, Singh, Rajat, Prystowsky, Michael B, Norton, Larry, Hazan, Rachel B (February 2022) Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer. Proceedings of the National Academy of Sciences of USA, 119 (8). e2107266119-e2107266119. ISSN 0027-8424

PDF 2022.Ren.breast_cancer.pdf Available under License Creative Commons Attribution. Download (3MB)

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.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal diseases & disorders > cancer > cancer types > breast cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organism description > animal > gender > female organism description > animal > gender organism description > animal > mammal organs, tissues, organelles, cell types and functions > organs types and functions > metabolism organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression > phosphorylation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction organs, tissues, organelles, cell types and functions > tissues types and functions diseases & disorders > cancer > cancer types
CSHL Authors:	Norton, Larry
Communities:	CSHL labs > Wigler lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	22 February 2022
Date Deposited:	07 Mar 2022 21:08
Last Modified:	17 Jan 2024 14:48
PMCID:	PMC8872779
URI:	https://repository.cshl.edu/id/eprint/40539

Actions (login required)

Administrator's edit/view item