Dataset Information

Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1?.

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 HIF1? and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Furthermore, B7-H3 promoted reactive oxygen species-dependent stabilization of HIF1? 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.

SUBMITTER: Lim S

PROVIDER: S-EPMC4874665 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α.

Lim Sangbin S Liu Hao H Madeira da Silva Luciana L Arora Ritu R Liu Zixing Z Phillips Joshua B JB Schmitt David C DC Vu Tung T McClellan Steven S Lin Yifeng Y Lin Wensheng W Piazza Gary A GA Fodstad Oystein O Tan Ming M

Cancer research 20160405 8

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 ...[more]

PMID: 27197253

Similar Datasets

Project description:Tumour metabolic reprogramming is pivotal for tumour survival and proliferation. Investigating potential molecular mechanisms within the heterogeneous and clinically aggressive triple-negative breast cancer (TNBC) subtype is essential to identifying novel therapeutic targets. Accordingly, we investigated the role of branched-chain α-keto acid dehydrogenase kinase (BCKDK) in promoting tumorigenesis in TNBC. We analysed The Cancer Genome Atlas dataset and immunohistochemically stained surgical specimens to investigate BCKDK expression and its prognostic implications in TNBC. The effects of BCKDK on tumorigenesis were assessed using cell viability, colony formation, apoptosis, and cell cycle assays, and subsequently validated in vivo. Metabolomic screening was performed via isotope tracer studies. The downstream target was confirmed using mass spectrometry and a co-immunoprecipitation experiment coupled with immunofluorescence analysis. Upstream transcription factors were also examined using chromatin immunoprecipitation and luciferase assays. BCKDK was upregulated in TNBC tumour tissues and associated with poor prognosis. BCKDK depletion led to reduced cell proliferation both in vitro and vivo. MYC-associated zinc finger protein (MAZ) was confirmed as the major transcription factor directly regulating BCKDK expression in TNBC. Mechanistically, BCKDK interacted with glucose-6-phosphate dehydrogenase (G6PD), leading to increased flux in the pentose phosphate pathway for macromolecule synthesis and detoxification of reactive oxygen species. Forced expression of G6PD rescued the growth defect in BCKDK-deficient cells. Notably, the small-molecule inhibitor of BCKDK, 3,6-dichlorobenzo(b)thiophene-2-carboxylic acid, exhibited anti-tumour effects in a patient-derived tumour xenograft model. Our findings hold significant promise for developing targeted therapies aimed at disrupting the MAZ/BCKDK/G6PD signalling pathway, offering potential advancements in treating TNBC through metabolic reprogramming.

Dataset Information

Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1?.

Publications

Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets