Involvement of SLC16A1/MCT1 and SLC16A3/MCT4 in l-lactate transport in the hepatocellular carcinoma cell line
Involvement of SLC16A1/MCT1 and SLC16A3/MCT4 in l-lactate transport in the hepatocellular carcinoma cell line
复制标题
SLC16A1/MCT1 和 SLC16A3/MCT4 参与肝细胞癌细胞系中 L-乳酸转运
DOI：
10.1002/bdd.2329
复制
发表时间：
2022
影响因子：
2.1
通讯作者：
Kobayashi M
中科院分区：
文献类型：
--
作者：
Mukai Y;Yamaguchi A;Sakuma T;Nadai T;Furugen A;Narumi K;Kobayashi M
已经报道了14种单羧酸转运蛋白（MCT）的亚型。在MCT亚型中，MCT 1、MCT 2和MCT 4在l-乳酸/质子共转运中发挥作用，并参与细胞内能量和pH的平衡。因此，MCT 1、MCT 2和MCT 4与正常和病理细胞的能量代谢过程相关。在本研究中，我们评估了肝细胞癌（HCC）细胞中MCT 1、MCT 2和MCT 4的表达以及这三种MCT亚型对tol-乳酸摄取的贡献。在HepG 2和Huh-7细胞中，l-乳酸转运具有pH依赖性，这是MCT 1、MCT 2和MCT 4的特征。此外，在HepG 2和Huh-7细胞中，MCT 1和MCT 4抑制剂选择性抑制L-乳酸摄取。HepG 2细胞的动力学分析表明，L-乳酸摄取是双相的。尽管HepG 2细胞中MCT 1和MCT 4的敲低降低了l-乳酸的摄取，但MCT 2的敲低对l-乳酸的摄取没有影响。因此，我们得出结论，在pH 6.0时，MCT 1和MCT 4均参与HepG 2和Huh-7细胞中l-乳酸的转运。相比之下，与HCC细胞系相比，PXB细胞（从人源化小鼠肝脏新鲜分离的肝细胞）在pH 6.0时显示出较低的MCT 4表达和l-乳酸摄取。总之，在HCC细胞中促进tol-乳酸转运的MCT 4与正常肝细胞相比在HCC中显著不同，并且具有作为HCC治疗靶点的潜力。
Fourteen isoforms of the monocarboxylate transporter (MCT) have been reported. Among the MCT isoforms, MCT1, MCT2, and MCT4 play a role inl‐lactate/proton cotransport and are involved in the balance of intracellular energy and pH. Therefore, MCT1, MCT2, and MCT4 are associated with energy metabolism processes in normal and pathological cells. In the present study, we evaluated the expression of MCT1, MCT2, and MCT4 and the contribution of these three MCT isoforms tol‐lactate uptake in hepatocellular carcinoma (HCC) cells. In HepG2 and Huh‐7 cells,l‐lactate transport was pH‐dependent, which is characteristic of MCT1, MCT2, and MCT4. Furthermore,l‐lactate uptake was selectively inhibited by MCT1 and MCT4 inhibitors in HepG2 and Huh‐7 cells. Kinetic analysis of HepG2 cells demonstrated thatl‐lactate uptake was biphasic. Although the knockdown of MCT1 and MCT4 in the HepG2 cells decreased the uptake ofl‐lactate, the knockdown of MCT2 had no effect on the uptake ofl‐lactate. Consequently, we concluded that both MCT1 and MCT4 were involved in the transport ofl‐lactate in HepG2 and Huh‐7 cells at pH 6.0. In contrast, PXB‐cells, freshly isolated hepatocytes from humanized mouse livers, showed lower MCT4 expression andl‐lactate uptake at pH 6.0 compared to that in HCC cell lines. In conclusion, MCT4, which contributes tol‐lactate transport in HCC cells, is significantly different in HCC compared to normal hepatocytes, and has potential as a target for HCC treatment.