Lai Sheng-Wei, Lin Hui-Jung, Liu Yu-Shu, Yang Liang-Yo, Lu Dah-Yuu
Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.
Department of Pharmacology, School of Medicine, China Medical University, Taichung 40402, Taiwan.
Cancers (Basel). 2020 Feb 7;12(2):380. doi: 10.3390/cancers12020380.
Glioblastoma (GBM) is characterized by severe hypoxic and acidic stress in an abnormal microenvironment. Monocarboxylate transporter (MCT)4, a pH-regulating protein, plays an important role in pH homeostasis of the glycolytic metabolic pathways in cancer cells. The present study showed that GBM exposure to hypoxic conditions increased MCT4 expression. We further analyzed the glioma patient database and found that MCT4 was significantly overexpressed in patients with GBM, and the MCT4 levels positively correlated with the clinico-pathological grades of gliomas. We further found that MCT4 knockdown abolished the hypoxia-enhanced of GBM cell motility and monocyte adhesion. However, the overexpression of MCT4 promoted GBM cell migration and monocyte adhesion activity. Our results also revealed that MCT4-regulated GBM cell motility and monocyte adhesion are mediated by activation of the serine/threonine-specific protein kinase (AKT), focal adhesion kinase (FAK), and epidermal growth factor receptor (EGFR) signaling pathways. Moreover, hypoxia mediated the acetylated signal transducer and activator of transcription (STAT)3 expression and regulated the transcriptional activity of hypoxia inducible factor (HIF)-1α in GBM cell lines. In a GBM mouse model, MCT4 was significantly increased in the tumor necrotic tissues. These findings raise the possibility for the development of novel therapeutic strategies targeting MCT4.
胶质母细胞瘤（GBM）的特征是在异常微环境中存在严重的缺氧和酸性应激。单羧酸转运蛋白（MCT）4是一种调节pH值的蛋白，在癌细胞糖酵解代谢途径的pH值稳态中起重要作用。本研究表明，暴露于缺氧条件下的GBM会增加MCT4的表达。我们进一步分析了胶质瘤患者数据库，发现MCT4在GBM患者中显著过表达，且MCT4水平与胶质瘤的临床病理分级呈正相关。我们还发现，敲低MCT4可消除缺氧增强的GBM细胞运动性和单核细胞黏附。然而，MCT4的过表达促进了GBM细胞迁移和单核细胞黏附活性。我们的结果还表明，MCT4调节的GBM细胞运动性和单核细胞黏附是由丝氨酸/苏氨酸特异性蛋白激酶（AKT）、黏着斑激酶（FAK）和表皮生长因子受体（EGFR）信号通路的激活介导的。此外，缺氧介导了乙酰化信号转导和转录激活因子（STAT）3的表达，并调节了GBM细胞系中缺氧诱导因子（HIF）-1α的转录活性。在GBM小鼠模型中，肿瘤坏死组织中的MCT4显著增加。这些发现为开发针对MCT4的新型治疗策略提供了可能性。
