Duan Li-Mei, Liu Jia-Yu, Yu Chao-Wen, Fan Jia-Xin, Li Ting, Yang Jin-Xiao, Zheng Yong-Bo, Liu Feng-Chun, He Zhen-Ting, Yuan Hong-Ling, Wu Xiao-Hou, Luo Chun-Li
Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), School of Laboratory Medicine, Chongqing Medical University Chongqing 400016, China.
Department of Urology, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China.
Am J Cancer Res. 2020 Jan 1;10(1):196-210. eCollection 2020.
The metabolic reprogramming is an important basis for the development of many tumors, including prostate cancer (PCa). Metabolic changes in many amino acids consist of serine and glycine affect the biological behavior of them. Phospholipase C epsilon (PLCε) plays an important role as an oncogene. However, its role in regulating amino acid metabolism remains unclear. In this study, results found significantly positive correlation between PLCε and Yes-associated protein (YAP) in PCa tissues. LC-MS/MS and GC-MS results further displayed abnormally elevated levels of serine, glycine and its some downstream metabolites in the blood of PCa patients. Secondly, PLCε knockdown can inhibit serine/glycine producing and proliferation of PCa both in vivo and in vitro. Mechanistically, PLCε may affect the serine/glycine metabolism by regulating dephosphorylation and nuclear translocation of YAP. More interestingly, verteporfin (VP, a specific inhibitor of YAP) could effectively enhance the PLCε-depletion induced inhibition of serine/glycine secretion and growth. Overall, this research revealed the possibility of anomalous serine/glycine levels in the blood for the diagnosis of PCa, identified the important role of the PLCε/YAP axis in regulating serine/glycine metabolism, cell proliferation and tumor growth, and suggested the combination of VP with PLCε-depletion may provide a new idea for the treatment of PCa.
代谢重编程是包括前列腺癌（PCa）在内的许多肿瘤发生发展的重要基础。包括丝氨酸和甘氨酸在内的多种氨基酸的代谢变化会影响它们的生物学行为。磷脂酶Cε（PLCε）作为一种癌基因发挥着重要作用。然而，其在调节氨基酸代谢中的作用仍不清楚。在本研究中，结果发现PCa组织中PLCε与Yes相关蛋白（YAP）之间存在显著正相关。液相色谱-串联质谱（LC-MS/MS）和气相色谱-质谱（GC-MS）结果进一步显示，PCa患者血液中丝氨酸、甘氨酸及其一些下游代谢产物水平异常升高。其次，敲低PLCε在体内和体外均可抑制PCa的丝氨酸/甘氨酸生成和增殖。机制上，PLCε可能通过调节YAP的去磷酸化和核转位来影响丝氨酸/甘氨酸代谢。更有趣的是，维替泊芬（VP，YAP的特异性抑制剂）可有效增强PLCε缺失诱导的对丝氨酸/甘氨酸分泌和生长的抑制作用。总体而言，本研究揭示了血液中丝氨酸/甘氨酸水平异常用于PCa诊断的可能性，确定了PLCε/YAP轴在调节丝氨酸/甘氨酸代谢、细胞增殖和肿瘤生长中的重要作用，并表明VP与PLCε缺失联合应用可能为PCa治疗提供新思路。
