Fig. S1: Glucose uptake and lactate production in B7-H3 knockdown Fig. S2: Growth inhibition W/O B7-H3 Fig S3: Proliferation assay in glucose deprivation. Fig. S4: Expression in B7-H3 knockdown w/o CoCl2. Fig. S5: mRNA levels. Fig. S6: Reduction of ROS by ROS scavenger in B7-H3 overexpression. Fig. S7: G6PD and SOD activity. Fig. S8: Growth Inhibition by ROS scavenger. Fig. S9: Immunohistochemistry analysis of xenograft tumors.
Funding
Cancer Research Foundation
NIH
The Radiumhospitalets Legater
National Natural Science Foundation of China Projects
ARTICLE 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.
