Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α.
Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α.
复制标题
免疫调节蛋白B7-H3通过ROS介导的HIF1α稳定化在癌细胞中重新编码葡萄糖代谢。
DOI：
10.1158/0008-5472.can-15-1538
复制
发表时间：
2016-04-15
期刊：
影响因子：
11.2
通讯作者：
Tan M
中科院分区：
文献类型：
--
作者：
Lim S;Liu H;Madeira da Silva L;Arora R;Liu Z;Phillips JB;Schmitt DC;Vu T;McClellan S;Lin Y;Lin W;Piazza GA;Fodstad O;Tan M
B7-H3是由T细胞表达的免疫调节性跨膜糖蛋白B7家族的成员。虽然B7-H3过表达与多种癌症的不良结局相关，但它在T细胞外也具有免疫独立作用，其对癌症的确切机制尚不清楚。在这项研究中，我们研究了B7-H3在体外和体内癌细胞代谢重编程中的作用。我们发现，B7-H3促进了瓦尔堡效应，证明了增加的葡萄糖摄取和乳酸产生的B7-H3表达细胞。B7-H3还增加了HIF-1α及其下游靶点LDHA和PDK 1的蛋白水平，这些酶是糖酵解途径中的关键酶。此外，B7-H3通过抑制应激激活转录因子Nrf 2及其靶基因（包括抗氧化剂SOD 1、SOD 2和PRX 3）的活性，促进了HIF-1α的ROS依赖性稳定。小鼠中人乳腺癌异种移植物的代谢成像证实B7-H3增强肿瘤葡萄糖摄取和肿瘤生长。总之，我们的研究结果阐明了B7-H3对癌症代谢的关键免疫独立贡献，为恶性进展中的B7家族免疫调节蛋白提供了一个全新的视角。
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 is 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 HIF-1α and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Further, B7-H3 promoted ROS-dependent stabilization of HIF-1α 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.