Division of General Zoology, Department of Biology, University of Kaiserslautern (TUK), D-67653, Kaiserslautern, Germany.
Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, 32610, USA.
Oncogene. 2020 Feb;39(8):1710-1723. doi: 10.1038/s41388-019-1098-6. Epub 2019 Nov 13.
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.
肿瘤细胞依赖糖酵解来满足其对能量的高需求。因此，它们会产生大量的乳酸和质子，这些质子通过单羧酸转运蛋白（MCT）被输出，支持酸性微环境的形成。本研究表明，碳酸酐酶 IX（CAIX）是癌细胞中主要的酸碱调节剂之一，在来自人类乳腺癌患者的组织样本中与 MCT1 和 MCT4 形成蛋白复合物，但在健康的乳腺组织中不存在。这种运输代谢物的形成需要 CAIX 与 MCT1/4 伴侣蛋白 CD147 的 Ig1 结构域结合，并且是 CAIX 介导的促进 MCT1/4 活性所必需的。针对 CD147-Ig1 结构域的抗体的应用会将 CAIX 从转运蛋白上置换下来，并抑制 CAIX 介导的质子偶联乳酸转运的促进作用。在癌细胞中，这种“代谢物破坏”会导致乳酸转运减少、糖酵解减少，最终导致细胞增殖减少。总之，该研究表明碳酸酐酶在人类肿瘤组织中与酸碱转运蛋白形成运输代谢物，并且可以利用这些相互作用来干扰肿瘤代谢和增殖。
