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.

doi:10.1073/pnas.2107266119

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

Journal Article · Tue Feb 22 00:00:00 EST 2022 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2107266119· OSTI ID:2419585

^[1]; Liang, Huizhi ^[2]; Galbo, Phillip M. ^[2]; ^[3]; ^[2]; ^[3]; ^[2]; Martinez-Lopez, Nuria ^[2]; Suyama, Kimita ^[2]; Benard, Outhiriaradjou ^[2]; Zheng, Wei ^[4]; Liu, Yang ^[2]; Albanese, Joseph ^[2]; ^[2]; Mar, Jessica C. ^[3]; ^[2]; ^[2]; ^[5]; ^[2]

Albert Einstein College of Medicine, Bronx, NY (United States); OSTI
Albert Einstein College of Medicine, Bronx, NY (United States)
Univ. of Queensland, Brisbane, QLD (Australia)
Icahn School of Medicine at Mount Sinai, New York, NY (United States)
Memorial Sloan Kettering Cancer Center, New York, NY (United States)

Redox regulation of breast cancer underlies malignant progression. Loss of the antioxidant glutathione peroxidase 2 in breast cancer cells increases reactive oxygen species, thereby activating hypoxia inducible factor-α (HIF1α) signaling. This in turn causes vascular malfunction, resulting in hypoxia and metabolic heterogeneity. HIF1α suppresses oxidative phosphorylation and stimulates glycolysis (the Warburg effect) in most of the tumor, except for one cancer subpopulation, which was capable of using both metabolic modalities. Hence, adopting a hybrid metabolic state may allow tumor cells to survive under aerobic or hypoxic conditions, a vulnerability that may be exploited for therapeutic targeting by either metabolic or redox-based strategies.

View Accepted Manuscript (DOE)

Research Organization:: Washington Univ., St. Louis, MO (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0001035

OSTI ID:: 2419585

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 8 Vol. 119; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

References (58)

Human Endomucin Is an Endothelial Marker Liu, Canhui; Shao, Zhi-Ming; Zhang, Liping Biochemical and Biophysical Research Communications, Vol. 288, Issue 1 https://doi.org/10.1006/bbrc.2001.5737	journal	October 2001
Reactive oxygen species-dependent signaling regulates cancer Weinberg, Frank; Chandel, Navdeep S. Cellular and Molecular Life Sciences, Vol. 66, Issue 23 https://doi.org/10.1007/s00018-009-0099-y	journal	July 2009
GPX2 underexpression indicates poor prognosis in patients with urothelial carcinomas of the upper urinary tract and urinary bladder Chang, I-Wei; Lin, Victor Chia-Hsiang; Hung, Chih-Hsin World Journal of Urology, Vol. 33, Issue 11 https://doi.org/10.1007/s00345-015-1522-7	journal	March 2015
An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients Györffy, Balazs; Lanczky, Andras; Eklund, Aron C. Breast Cancer Research and Treatment, Vol. 123, Issue 3 https://doi.org/10.1007/s10549-009-0674-9	journal	December 2009
Hypoxia and cancer Semenza, Gregg L. Cancer and Metastasis Reviews, Vol. 26, Issue 2 https://doi.org/10.1007/s10555-007-9058-y	journal	April 2007
Progression to Malignancy in the Polyoma Middle T Oncoprotein Mouse Breast Cancer Model Provides a Reliable Model for Human Diseases Lin, Elaine Y.; Jones, Joan G.; Li, Ping The American Journal of Pathology, Vol. 163, Issue 5 https://doi.org/10.1016/S0002-9440(10)63568-7	journal	November 2003
An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative Stress Harding, Heather P.; Zhang, Yuhong; Zeng, Huiquing Molecular Cell, Vol. 11, Issue 3 https://doi.org/10.1016/S1097-2765(03)00105-9	journal	March 2003
Choosing between glycolysis and oxidative phosphorylation: A tumor's dilemma? Jose, Caroline; Bellance, Nadège; Rossignol, Rodrigue Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol. 1807, Issue 6 https://doi.org/10.1016/j.bbabio.2010.10.012	journal	June 2011
Aggressive triple negative breast cancers have unique molecular signature on the basis of mitochondrial genetic and functional defects Guha, Manti; Srinivasan, Satish; Raman, Pichai Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Vol. 1864, Issue 4 https://doi.org/10.1016/j.bbadis.2018.01.002	journal	April 2018
Glutathione peroxidases in different stages of carcinogenesis Brigelius-Flohé, Regina; Kipp, Anna Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1790, Issue 11 https://doi.org/10.1016/j.bbagen.2009.03.006	journal	November 2009
Glutathione peroxidases Brigelius-Flohé, Regina; Maiorino, Matilde Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1830, Issue 5 https://doi.org/10.1016/j.bbagen.2012.11.020	journal	May 2013
Breast cancer stem cells and epithelial mesenchymal plasticity – Implications for chemoresistance Pinto, Cletus A.; Widodo, Edwin; Waltham, Mark Cancer Letters, Vol. 341, Issue 1 https://doi.org/10.1016/j.canlet.2013.06.003	journal	November 2013
Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer Cheung, Eric C.; DeNicola, Gina M.; Nixon, Colin Cancer Cell, Vol. 37, Issue 2 https://doi.org/10.1016/j.ccell.2019.12.012	journal	February 2020
Oxidative Stress in Cancer Hayes, John D.; Dinkova-Kostova, Albena T.; Tew, Kenneth D. Cancer Cell, Vol. 38, Issue 2 https://doi.org/10.1016/j.ccell.2020.06.001	journal	August 2020
Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states Simeonov, Kamen P.; Byrns, China N.; Clark, Megan L. Cancer Cell, Vol. 39, Issue 8 https://doi.org/10.1016/j.ccell.2021.05.005	journal	August 2021
Glucose metabolism and cancer Shaw, Reuben J. Current Opinion in Cell Biology, Vol. 18, Issue 6 https://doi.org/10.1016/j.ceb.2006.10.005	journal	December 2006
Hypoxia-Inducible Factors, Stem Cells, and Cancer Keith, Brian; Simon, M. Celeste Cell, Vol. 129, Issue 3 https://doi.org/10.1016/j.cell.2007.04.019	journal	May 2007
Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization Mazzone, Massimiliano; Dettori, Daniela; Leite de Oliveira, Rodrigo Cell, Vol. 136, Issue 5 https://doi.org/10.1016/j.cell.2009.01.020	journal	March 2009
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling Ray, Paul D.; Huang, Bo-Wen; Tsuji, Yoshiaki Cellular Signalling, Vol. 24, Issue 5 https://doi.org/10.1016/j.cellsig.2012.01.008	journal	May 2012
AMPK Maintains Cellular Metabolic Homeostasis through Regulation of Mitochondrial Reactive Oxygen Species Rabinovitch, Rebecca C.; Samborska, Bozena; Faubert, Brandon Cell Reports, Vol. 21, Issue 1 https://doi.org/10.1016/j.celrep.2017.09.026	journal	October 2017
Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation Brunelle, Joslyn K.; Bell, Eric L.; Quesada, Nancy M. Cell Metabolism, Vol. 1, Issue 6 https://doi.org/10.1016/j.cmet.2005.05.002	journal	June 2005
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption Papandreou, Ioanna; Cairns, Rob A.; Fontana, Lucrezia Cell Metabolism, Vol. 3, Issue 3 https://doi.org/10.1016/j.cmet.2006.01.012	journal	March 2006
PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer Dupuy, Fanny; Tabariès, Sébastien; Andrzejewski, Sylvia Cell Metabolism, Vol. 22, Issue 4 https://doi.org/10.1016/j.cmet.2015.08.007	journal	October 2015
Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling Luo, Ming; Shang, Li; Brooks, Michael D. Cell Metabolism, Vol. 28, Issue 1 https://doi.org/10.1016/j.cmet.2018.06.006	journal	July 2018
ROS Function in Redox Signaling and Oxidative Stress Schieber, Michael; Chandel, Navdeep S. Current Biology, Vol. 24, Issue 10 https://doi.org/10.1016/j.cub.2014.03.034	journal	May 2014
Oxygen Sensing by Metazoans: The Central Role of the HIF Hydroxylase Pathway Kaelin, William G.; Ratcliffe, Peter J. Molecular Cell, Vol. 30, Issue 4 https://doi.org/10.1016/j.molcel.2008.04.009	journal	May 2008
Sirtuin 1 Modulates Cellular Responses to Hypoxia by Deacetylating Hypoxia-Inducible Factor 1α Lim, Ji-Hong; Lee, Yoon-Mi; Chun, Yang-Sook Molecular Cell, Vol. 38, Issue 6 https://doi.org/10.1016/j.molcel.2010.05.023	journal	June 2010
Control of the hypoxic response through regulation of mRNA translation Wouters, Bradly G.; van den Beucken, Twan; Magagnin, Michael G. Seminars in Cell & Developmental Biology, Vol. 16, Issue 4-5 https://doi.org/10.1016/j.semcdb.2005.03.009	journal	August 2005
New aspects of the Warburg effect in cancer cell biology Bensinger, Steven J.; Christofk, Heather R. Seminars in Cell & Developmental Biology, Vol. 23, Issue 4 https://doi.org/10.1016/j.semcdb.2012.02.003	journal	June 2012
Wnt Proteins Are Self-Renewal Factors for Mammary Stem Cells and Promote Their Long-Term Expansion in Culture Zeng, Yi Arial; Nusse, Roel Cell Stem Cell, Vol. 6, Issue 6 https://doi.org/10.1016/j.stem.2010.03.020	journal	June 2010
HIF-1 regulation: not so easy come, easy go Koh, Mei Yee; Spivak-Kroizman, Taly R.; Powis, Garth Trends in Biochemical Sciences, Vol. 33, Issue 11 https://doi.org/10.1016/j.tibs.2008.08.002	journal	November 2008
Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy Semenza, Gregg L. Trends in Pharmacological Sciences, Vol. 33, Issue 4 https://doi.org/10.1016/j.tips.2012.01.005	journal	April 2012
Metabolic Fitness and Plasticity in Cancer Progression McGuirk, Shawn; Audet-Delage, Yannick; St-Pierre, Julie Trends in Cancer, Vol. 6, Issue 1 https://doi.org/10.1016/j.trecan.2019.11.009	journal	January 2020
Targeting Dependency on the GPX4 Lipid Peroxide Repair Pathway for Cancer Therapy Liu, Hengrui; Schreiber, Stuart L.; Stockwell, Brent R. Biochemistry, Vol. 57, Issue 14 https://doi.org/10.1021/acs.biochem.8b00307	journal	March 2018
A role for VEGF as a negative regulator of pericyte function and vessel maturation Greenberg, Joshua I.; Shields, David J.; Barillas, Samuel G. Nature, Vol. 456, Issue 7223 https://doi.org/10.1038/nature07424	journal	November 2008
Molecular mechanisms and clinical applications of angiogenesis Carmeliet, Peter; Jain, Rakesh K. Nature, Vol. 473, Issue 7347 https://doi.org/10.1038/nature10144	journal	May 2011
Dimensionality reduction for visualizing single-cell data using UMAP Becht, Etienne; McInnes, Leland; Healy, John Nature Biotechnology, Vol. 37, Issue 1 https://doi.org/10.1038/nbt.4314	journal	December 2018
Cancer metabolism: fatty acid oxidation in the limelight Carracedo, Arkaitz; Cantley, Lewis C.; Pandolfi, Pier Paolo Nature Reviews Cancer, Vol. 13, Issue 4 https://doi.org/10.1038/nrc3483	journal	February 2013
Single-cell analysis tools for drug discovery and development Heath, James R.; Ribas, Antoni; Mischel, Paul S. Nature Reviews Drug Discovery, Vol. 15, Issue 3 https://doi.org/10.1038/nrd.2015.16	journal	December 2015
ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth Bi, Meixia; Naczki, Christine; Koritzinsky, Marianne The EMBO Journal, Vol. 24, Issue 19 https://doi.org/10.1038/sj.emboj.7600777	journal	September 2005
Normalization of the tumor vasculature through oncogenic inhibition: An emerging paradigm in tumor biology Goel, Shom; Fukumura, Dai; Jain, Rakesh K. Proceedings of the National Academy of Sciences, Vol. 109, Issue 20 https://doi.org/10.1073/pnas.1203794109	journal	May 2012
Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways Jia, Dongya; Lu, Mingyang; Jung, Kwang Hwa Proceedings of the National Academy of Sciences, Vol. 116, Issue 9 https://doi.org/10.1073/pnas.1816391116	journal	February 2019
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation Vander Heiden, M. G.; Cantley, L. C.; Thompson, C. B. Science, Vol. 324, Issue 5930 https://doi.org/10.1126/science.1160809	journal	May 2009
The Yin and Yang of Nrf2-Regulated Selenoproteins in Carcinogenesis Brigelius-Flohé, Regina; Müller, Mike; Lippmann, Doris International Journal of Cell Biology, Vol. 2012 https://doi.org/10.1155/2012/486147	journal	January 2012
Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity Kong, Dehe; Park, Eun Jung; Stephen, Andrew G. Cancer Research, Vol. 65, Issue 19 https://doi.org/10.1158/0008-5472.CAN-05-1235	journal	October 2005
Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation Yu, Linglin; Lu, Mingyang; Jia, Dongya Cancer Research, Vol. 77, Issue 7 https://doi.org/10.1158/0008-5472.CAN-16-2074	journal	April 2017
Impact of Galectins in Resistance to Anticancer Therapies Navarro, Pilar; Martínez-Bosch, Neus; Blidner, Ada G. Clinical Cancer Research, Vol. 26, Issue 23 https://doi.org/10.1158/1078-0432.CCR-18-3870	journal	December 2020
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations Semenza, Gregg L. Journal of Clinical Investigation, Vol. 123, Issue 9 https://doi.org/10.1172/JCI67230	journal	September 2013
Chemotherapy-Associated Oxidative Stress: Impact on Chemotherapeutic Effectiveness Conklin, Kenneth A. Integrative Cancer Therapies, Vol. 3, Issue 4 https://doi.org/10.1177/1534735404270335	journal	December 2004
Hypoxia-Induced Angiogenesis: Good and Evil Krock, B. L.; Skuli, N.; Simon, M. C. Genes & Cancer, Vol. 2, Issue 12 https://doi.org/10.1177/1947601911423654	journal	September 2011
Clinicopathological and prognostic significance of GPX2 protein expression in esophageal squamous cell carcinoma Lei, Zhijin; Tian, Dongping; Zhang, Chong BMC Cancer, Vol. 16, Issue 1 https://doi.org/10.1186/s12885-016-2462-3	journal	July 2016
The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state Kurutas, Ergul Belge Nutrition Journal, Vol. 15, Issue 1 https://doi.org/10.1186/s12937-016-0186-5	journal	December 2015
Metabolic profiling of triple-negative breast cancer cells reveals metabolic vulnerabilities Lanning, Nathan J.; Castle, Joshua P.; Singh, Simar J. Cancer & Metabolism, Vol. 5, Issue 1 https://doi.org/10.1186/s40170-017-0168-x	journal	August 2017
Reactive oxygen species as double-edged swords in cellular processes: low-dose cell signaling versus high-dose toxicity Martin, K. R.; Barrett, J. C. Human & Experimental Toxicology, Vol. 21, Issue 2 https://doi.org/10.1191/0960327102ht213oa	journal	February 2002
The Role of Hypoxia-Induced Factors in Tumor Progression Vaupel, Peter The Oncologist, Vol. 9, Issue S5 https://doi.org/10.1634/theoncologist.9-90005-10	journal	November 2004
Galectin-3 supports stemness in ovarian cancer stem cells by activation of the Notch1 intracellular domain Kang, Hyeok Gu; Kim, Da-Hyun; Kim, Seok-Jun Oncotarget, Vol. 7, Issue 42 https://doi.org/10.18632/oncotarget.11920	journal	September 2016
Reactive oxygen species in cancer Liou, Geou-Yarh; Storz, Peter Free Radical Research, Vol. 44, Issue 5 https://doi.org/10.3109/10715761003667554	journal	January 2010
Cancer Stem Cell Metabolism and Potential Therapeutic Targets Snyder, Vusala; Reed-Newman, Tamika C.; Arnold, Levi Frontiers in Oncology, Vol. 8 https://doi.org/10.3389/fonc.2018.00203	journal	June 2018

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