CAIX forms a transport metabolon with monocarboxylate transporters in human breast cancer cells
CAIX forms a transport metabolon with monocarboxylate transporters in human breast cancer cells
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DOI：
10.1038/s41388-019-1098-6
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发表时间：
2020-02-01
期刊：
影响因子：
8
通讯作者：
Becker, Holger M.
中科院分区：
文献类型：
--
作者：
Ames, Samantha;Andring, Jacob T.;Becker, Holger M.
肿瘤细胞依赖糖酵解来满足它们对能量的更高需求。因此，它们产生大量的乳酸和质子，这些乳酸和质子通过单羧酸转运体(MCT)输出，支持酸性微环境的形成。本研究表明，癌细胞中主要的酸/碱调节因子之一的碳酸酐酶IX(CAIX)在乳腺癌患者的组织样本中与MCT1和MCT4形成蛋白质复合体，而在正常乳腺组织中不存在。这种转运代谢子的形成需要CAIX与MCT1/4伴侣CD147的IG1结构域结合，这是CAIX介导的MCT1/4活性促进所必需的。针对CD147-IG1结构域的抗体的应用，取代了转运体上的CAIX，并抑制了CAIX介导的质子偶联乳酸转运。在癌细胞中，这种“代谢紊乱”导致乳酸转运减少，糖酵解减少，最终抑制细胞增殖。综上所述，这项研究表明，碳酸酐酶在人类肿瘤组织中与酸/碱转运体形成运输代谢物，这些相互作用可以被用来干扰肿瘤的新陈代谢和增殖。
Tumor cells rely on glycolysis to meet their elevated demand for energy. Thereby they produce significant amounts of lactate and protons, which are exported via monocarboxylate transporters (MCTs), supporting the formation of an acidic microenvironment. The present study demonstrates that carbonic anhydrase IX (CAIX), one of the major acid/base regulators in cancer cells, forms a protein complex with MCT1 and MCT4 in tissue samples from human breast cancer patients, but not healthy breast tissue. Formation of this transport metabolon requires binding of CAIX to the Ig1 domain of the MCT1/4 chaperon CD147 and is required for CAIX-mediated facilitation of MCT1/4 activity. Application of an antibody, directed against the CD147-Ig1 domain, displaces CAIX from the transporter and suppresses CAIX-mediated facilitation of proton-coupled lactate transport. In cancer cells, this "metabolon disruption" results in a decrease in lactate transport, reduced glycolysis, and ultimately reduced cell proliferation. Taken together, the study shows that carbonic anhydrases form transport metabolons with acid/base transporters in human tumor tissue and that these interactions can be exploited to interfere with tumor metabolism and proliferation.