Institute of Cellular and System Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County, 35053, Taiwan.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
J Biomed Sci. 2022 Nov 7;29(1):93. doi: 10.1186/s12929-022-00878-z.
Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of SDH subunits (SDHD and SDHB) in hereditary tumors such as paraganglioma or reduction of SDHB expression in cancer results in matrix succinate accumulation which is transported to cytoplasma and secreted into the extracellular milieu. Excessive cytosolic succinate is known to stabilize hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase. Recent reports indicate that cancer-secreted succinate enhances cancer cell migration and promotes cancer metastasis by activating succinate receptor-1 (SUCNR-1)-mediated signaling and transcription pathways. Cancer-derived extracellular succinate enhances cancer cell and macrophage migration through SUCNR-1 → PI-3 K → HIF-1α pathway. Extracellular succinate induces tumor angiogenesis through SUCNR-1-mediated ERK1/2 and STAT3 activation resulting in upregulation of vascular endothelial growth factor (VEGF) expression. Succinate increases SUCNR-1 expression in cancer cells which is considered as a target for developing new anti-metastasis drugs. Furthermore, serum succinate which is elevated in cancer patients may be a theranostic biomarker for selecting patients for SUCNR-1 antagonist therapy.
琥珀酸是三羧酸（TCA）循环中间产物，通常局限于线粒体基质中。它是琥珀酸脱氢酶（SDH）的底物。在遗传性肿瘤（如副神经节瘤）中，SDH 亚基（SDHD 和 SDHB）的突变或癌症中 SDHB 表达的减少导致基质琥珀酸积累，然后被转运到细胞质并分泌到细胞外环境中。已知过量的细胞质琥珀酸通过抑制脯氨酰羟化酶来稳定缺氧诱导因子-1α（HIF-1α）。最近的报道表明，癌细胞分泌的琥珀酸通过激活琥珀酸受体-1（SUCNR-1）介导的信号转导和转录途径，增强癌细胞迁移并促进癌症转移。细胞外琥珀酸通过 SUCNR-1→PI-3K→HIF-1α 途径增强癌细胞和巨噬细胞迁移。细胞外琥珀酸通过 SUCNR-1 介导的 ERK1/2 和 STAT3 激活诱导肿瘤血管生成，从而上调血管内皮生长因子（VEGF）的表达。琥珀酸增加了癌细胞中的 SUCNR-1 表达，这被认为是开发新的抗转移药物的靶点。此外，癌症患者血清中琥珀酸升高，可能是选择 SUCNR-1 拮抗剂治疗患者的治疗标志物。
