Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via Salvatore Allende, 84081, Baronissi Salerno, Italy.
Institute of Endocrinology and Experimental Oncology, IEOS CNR, Via Pansini 5, 80131, Naples, Italy.
Sci Rep. 2017 Oct 26;7(1):14123. doi: 10.1038/s41598-017-14495-6.
Glioblastoma (GBM), the most aggressive brain cancer, is highly dependent on the mevalonate (MVA) pathway for the synthesis of lipid moieties critical for cell proliferation but the function and regulation of key intermediate enzymes like farnesyl-diphosphate synthase (FDPS), up to now, remained unknown. A deregulated expression and activity of FDPS was the central research idea of the present study. FDPS mRNA, protein and enzyme activity were analyzed in a cohort of stage III-IV glioma patients (N = 49) and primary derived cells. FDPS silencing helped to clarify its function in the maintenance of malignant phenotype. Interestingly, compared to tumor-free peripheral (TFB) brain and normal human astrocytes (NHA), FDPS protein expression and enzyme activity were detected at high degree in tumor mass where a correlation with canonical oncogenic signaling pathways such as STAT3, ERK and AKT was also documented. Further, FDPS knockdown in U87 and GBM primary cells but not in NHA, enhanced apoptosis. With the effort to develop a more refined map of the connectivity between signal transduction pathways and metabolic networks in cancer FDPS as a new candidate metabolic oncogene in glioblastoma, might suggest to further target MVA pathway as valid therapeutic tool.
胶质母细胞瘤（GBM）是最具侵袭性的脑癌，其脂质部分的合成严重依赖于甲羟戊酸（MVA）途径，这些脂质对于细胞增殖至关重要，但迄今为止，关键中间酶如法呢基二磷酸合酶（FDPS）的功能和调节仍不清楚。本研究的核心研究思路是 FDPS 的表达和活性失调。在 III-IV 期胶质母细胞瘤患者队列（N=49）和原代衍生细胞中分析了 FDPS mRNA、蛋白和酶活性。FDPS 沉默有助于阐明其在维持恶性表型中的功能。有趣的是，与无肿瘤外周脑（TFB）和正常人类星形胶质细胞（NHA）相比，FDPS 蛋白表达和酶活性在肿瘤组织中高度检测到，并且还记录了与经典致癌信号通路如 STAT3、ERK 和 AKT 的相关性。此外，在 U87 和 GBM 原代细胞中敲低 FDPS 而不是在 NHA 中敲低，可增强细胞凋亡。为了进一步开发癌症中信号转导途径和代谢网络之间更精细的连接图，FDPS 作为胶质母细胞瘤中的新候选代谢癌基因，可能提示进一步将 MVA 途径作为有效的治疗工具。
