Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong 226001, China; Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
Institute of Molecular Biosciences, University of Graz, Graz 8010, Austria.
EBioMedicine. 2020 Mar;53:102696. doi: 10.1016/j.ebiom.2020.102696. Epub 2020 Mar 3.
Tumor cells display metabolic changes that correlate with malignancy, including an elevated hydrolysis of monoacylglycerol (MAG) in various cancer types. However, evidence is absent for the relationship between MAG lipolysis and NSCLC.
MAG hydrolase activity assay, migration, invasion, proliferation, lipids quantification, and transactivation assays were performed in vitro. Tumor xenograft studies and lung metastasis assays were examined in vivo. The correlations of MAGL/ABHD6 expression in cancerous tissues with the clinicopathological characteristics and survival of NSCLC patients were validated.
ABHD6 functions as the primary MAG lipase and an oncogene in NSCLC. MAG hydrolase activities were more than 11-fold higher in cancerous lung tissues than in paired non-cancerous tissues derived from NSCLC patients. ABHD6, instead of MAGL, was significantly associated with advanced tumor node metastasis (TNM) stage (HR, 1.382; P = 0.004) and had a negative impact on the overall survival of NSCLC patients (P = 0.001). ABHD6 silencing reduced migration and invasion of NSCLC cells in vitro as well as metastatic seeding and tumor growth in vivo. Conversely, ectopic overexpression of ABHD6 provoked the pathogenic potential. ABHD6 blockade significantly induced intracellular MAG accumulation which activated PPARα/γ signaling and inhibited cancer pathophysiology.
The present study provide evidence for a previously uncovered pro-oncogenic function of ABHD6 in NSCLC, with the outlined metabolic mechanisms shedding light on new potential strategies for anticancer therapy. FUND: This work was supported by the Project for Major New Drug Innovation and Development (2015ZX09501010 and 2018ZX09711001-002-003).
肿瘤细胞表现出与恶性肿瘤相关的代谢变化，包括各种癌症类型中单酰基甘油（MAG）的水解增加。然而，MAG 脂解与非小细胞肺癌（NSCLC）之间的关系尚无证据。
在体外进行 MAG 水解酶活性测定、迁移、侵袭、增殖、脂质定量和转激活测定。在体内进行肿瘤异种移植研究和肺转移测定。验证 MAGL/ABHD6 在癌组织中的表达与 NSCLC 患者的临床病理特征和生存的相关性。
ABHD6 是 NSCLC 中主要的 MAG 脂肪酶和癌基因。癌症组织中的 MAG 水解酶活性比来自 NSCLC 患者的配对非癌组织高 11 倍以上。ABHD6 而不是 MAGL，与晚期肿瘤淋巴结转移（TNM）分期显著相关（HR，1.382；P=0.004），对 NSCLC 患者的总生存有负面影响（P=0.001）。ABHD6 沉默减少了 NSCLC 细胞在体外的迁移和侵袭，以及转移定植和体内肿瘤生长。相反，ABHD6 的异位过表达引发了致病潜力。ABHD6 阻断显著诱导细胞内 MAG 积累，激活 PPARα/γ 信号通路并抑制癌症病理生理。
本研究为 ABHD6 在 NSCLC 中的先前未被发现的促癌功能提供了证据，所概述的代谢机制为癌症治疗提供了新的潜在策略。资金：这项工作得到了重大新药创新和开发项目（2015ZX09501010 和 2018ZX09711001-002-003）的支持。
