Roland Christina L, Arumugam Thiruvengadam, Deng Defeng, Liu Shi He, Philip Bincy, Gomez Sobeyda, Burns William R, Ramachandran Vijaya, Wang Huamin, Cruz-Monserrate Zobeida, Logsdon Craig D
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2014 Sep 15;74(18):5301-10. doi: 10.1158/0008-5472.CAN-14-0319. Epub 2014 Jun 13.
The mechanisms that allow cancer cells to adapt to the typical tumor microenvironment of low oxygen and glucose and high lactate are not well understood. GPR81 is a lactate receptor recently identified in adipose and muscle cells that has not been investigated in cancer. In the current study, we examined GPR81 expression and function in cancer cells. We found that GPR81 was present in colon, breast, lung, hepatocellular, salivary gland, cervical, and pancreatic carcinoma cell lines. Examination of tumors resected from patients with pancreatic cancer indicated that 94% (148 of 158) expressed high levels of GPR81. Functionally, we observed that the reduction of GPR81 levels using shRNA-mediated silencing had little effect on pancreatic cancer cells cultured in high glucose, but led to the rapid death of cancer cells cultured in conditions of low glucose supplemented with lactate. We also observed that lactate addition to culture media induced the expression of genes involved in lactate metabolism, including monocarboxylase transporters in control, but not in GPR81-silenced cells. In vivo, GPR81 expression levels correlated with the rate of pancreatic cancer tumor growth and metastasis. Cells in which GPR81 was silenced showed a dramatic decrease in growth and metastasis. Implantation of cancer cells in vivo was also observed to lead to greatly elevated levels of GPR81. These data support that GPR81 is important for cancer cell regulation of lactate transport mechanisms. Furthermore, lactate transport is important for the survival of cancer cells in the tumor microenvironment. Cancer Res; 74(18); 5301-10. ©2014 AACR.
癌细胞适应低氧、低糖和高乳酸的典型肿瘤微环境的机制尚不清楚。GPR81是最近在脂肪和肌肉细胞中发现的一种乳酸受体，尚未在癌症中进行研究。在本研究中，我们检测了GPR81在癌细胞中的表达和功能。我们发现GPR81存在于结肠、乳腺、肺、肝细胞、唾液腺、宫颈和胰腺癌细胞系中。对胰腺癌患者切除的肿瘤进行检测表明，94%（158例中的148例）表达高水平的GPR81。在功能上，我们观察到使用shRNA介导的沉默降低GPR81水平对在高糖环境中培养的胰腺癌细胞影响不大，但导致在补充乳酸的低糖条件下培养的癌细胞迅速死亡。我们还观察到，向培养基中添加乳酸可诱导参与乳酸代谢的基因表达，包括对照组中的单羧酸转运体，但在GPR81沉默的细胞中则不然。在体内，GPR81表达水平与胰腺癌肿瘤生长和转移速率相关。GPR81沉默的细胞在生长和转移方面显著降低。体内植入癌细胞还观察到GPR81水平大幅升高。这些数据支持GPR81对癌细胞乳酸转运机制的调节很重要。此外，乳酸转运对肿瘤微环境中癌细胞的存活很重要。《癌症研究》；74(18)；5301 - 10。©2014美国癌症研究协会。
