title: Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α.
abstract: B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3-expressing cells. B7-H3 also increased the protein levels of HIF1α and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Furthermore, B7-H3 promoted reactive oxygen species-dependent stabilization of HIF1α by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression. Cancer Res; 76(8); 2231-42. ©2016 AACR.
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Sangbin
authors.initials: S
authors.lastname: Lim
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama. Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China. mtan@health.southalabama.edu liuhaoy@hotmail.com Oystein.Fodstad@rr-research.no.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Luciana
authors.initials: L
authors.lastname: Madeira da Silva
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Ritu
authors.initials: R
authors.lastname: Arora
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Zixing
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Phillips
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: David C
authors.initials: DC
authors.lastname: Schmitt
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Tung
authors.initials: T
authors.lastname: Vu
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Steven
authors.initials: S
authors.lastname: McClellan
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Lin
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama. Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, and Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. mtan@health.southalabama.edu liuhaoy@hotmail.com Oystein.Fodstad@rr-research.no.
authors.forename: Oystein
authors.initials: O
authors.lastname: Fodstad
authors.affiliation: Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama. Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama. mtan@health.southalabama.edu liuhaoy@hotmail.com Oystein.Fodstad@rr-research.no.
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
mesh_terms: D000818:Animals; D060887:B7 Antigens / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005947:Glucose / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D060887:B7 Antigens; C423237:CD276 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D005947:Glucose