Deregulated expression and activity of Farnesyl Diphosphate Synthase (FDPS) in Glioblastoma.
Deregulated expression and activity of Farnesyl Diphosphate Synthase (FDPS) in Glioblastoma.
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DOI：
10.1038/s41598-017-14495-6
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发表时间：
2017-10-26
影响因子：
4.6
通讯作者：
Ciaglia E
中科院分区：
文献类型：
--
作者：
Abate M;Laezza C;Pisanti S;Torelli G;Seneca V;Catapano G;Montella F;Ranieri R;Notarnicola M;Gazzerro P;Bifulco M;Ciaglia E
胶质母细胞瘤（GBM）是最具侵袭性的脑癌，其高度依赖于甲羟戊酸（MVA）途径来合成对细胞增殖至关重要的脂质部分，但关键中间酶如法尼基二磷酸合酶（FDPS）的功能和调节至今仍不清楚。FDPS的表达和活性失调是本研究的中心研究思路。在III-IV期胶质瘤患者（N = 49）和原代衍生细胞的队列中分析FDPS mRNA、蛋白质和酶活性。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（TFB）脑和正常人星形胶质细胞（NHA）相比，在肿瘤块中检测到FDPS蛋白表达和酶活性，其中还记录了与典型致癌信号传导途径（如STAT 3，ERK和AKT）的相关性。此外，在U87和GBM原代细胞中而不是在NHA中的FDPS敲低增强了细胞凋亡。随着开发更精细的癌症信号转导通路和代谢网络之间的连接图的努力，FDPS作为胶质母细胞瘤中新的候选代谢癌基因，可能建议进一步靶向MVA通路作为有效的治疗工具。
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.
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p53调节人类胶质母细胞瘤多形的甲谷酸途径。
影响因子：
9
作者：
Laezza C;D'Alessandro A;Di Croce L;Picardi P;Ciaglia E;Pisanti S;Malfitano AM;Comegna M;Faraonio R;Gazzerro P;Bifulco M
通讯作者：
Bifulco M
影响因子：
3.9
作者：
Chaponis D;Barnes JW;Dellagatta JL;Kesari S;Fast E;Sauvageot C;Panagrahy D;Greene ER;Ramakrishna N;Wen PY;Kung AL;Stiles C;Kieran MW
通讯作者：
Kieran MW
影响因子：
3.7
作者：
Fukai J;Koizumi F;Nakao N
通讯作者：
Nakao N
影响因子：
50.3
作者：
Villa GR;Hulce JJ;Zanca C;Bi J;Ikegami S;Cahill GL;Gu Y;Lum KM;Masui K;Yang H;Rong X;Hong C;Turner KM;Liu F;Hon GC;Jenkins D;Martini M;Armando AM;Quehenberger O;Cloughesy TF;Furnari FB;Cavenee WK;Tontonoz P;Gahman TC;Shiau AK;Cravatt BF;Mischel PS
通讯作者：
Mischel PS
影响因子：
5.5
作者：
Ciaglia, Elena;Pisanti, Simona;Bifulco, Maurizio
通讯作者：
Bifulco, Maurizio