- 作者: Cheng-Chin Kuo, Jing-Yiing Wu & Kenneth K. Wu
- 作者服務機構: 1.Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 2.Institute of Biotechnology, National Tsing-Hua University College of Life Science, Hsinchu, Taiwan 3.Institute of Cellular and System Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County, 35053, Taiwan
- 中文摘要:
- 英文摘要:
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. - 中文關鍵字:
- 英文關鍵字: Succinate, Succinate receptor-1, G-protein-coupled receptor 91 (GPR91), Cancer metastasis, Hereditary paraganglioma, Succinate dehydrogenase