Rinaldi Laura, Sepe Maria, Delle Donne Rossella, Conte Kristel, Arcella Antonietta, Borzacchiello Domenica, Amente Stefano, De Vita Fernanda, Porpora Monia, Garbi Corrado, Oliva Maria A, Procaccini Claudio, Faicchia Deriggio, Matarese Giuseppe, Zito Marino Federica, Rocco Gaetano, Pignatiello Sara, Franco Renato, Insabato Luigi, Majello Barbara, Feliciello Antonio
Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, University Federico II, Naples, Italy.
I.R.C.C.S Neuromed, Pozzilli, Italy.
Cell Death Dis. 2017 Jun 1;8(6):e2842. doi: 10.1038/cddis.2017.241.
Mitochondria are the powerhouses of energy production and the sites where metabolic pathway and survival signals integrate and focus, promoting adaptive responses to hormone stimulation and nutrient availability. Increasing evidence suggests that mitochondrial bioenergetics, metabolism and signaling are linked to tumorigenesis. AKAP1 scaffolding protein integrates cAMP and src signaling on mitochondria, regulating organelle biogenesis, oxidative metabolism and cell survival. Here, we provide evidence that AKAP1 is a transcriptional target of Myc and supports the growth of cancer cells. We identify Sestrin2, a leucine sensor and inhibitor of the mammalian target of rapamycin (mTOR), as a novel component of the complex assembled by AKAP1 on mitochondria. Downregulation of AKAP1 impaired mTOR pathway and inhibited glioblastoma growth. Both effects were reversed by concomitant depletion of AKAP1 and sestrin2. High levels of AKAP1 were found in a wide variety of high-grade cancer tissues. In lung cancer, AKAP1 expression correlates with high levels of Myc, mTOR phosphorylation and reduced patient survival. Collectively, these data disclose a previously unrecognized role of AKAP1 in mTOR pathway regulation and cancer growth. AKAP1/mTOR signal integration on mitochondria may provide a new target for cancer therapy.
线粒体是能量产生的动力源，也是代谢途径和生存信号整合与聚焦的场所，促进对激素刺激和营养可利用性的适应性反应。越来越多的证据表明，线粒体生物能量学、代谢和信号传导与肿瘤发生有关。AKAP1支架蛋白在线粒体上整合cAMP和src信号，调节细胞器生物发生、氧化代谢和细胞存活。在此，我们提供证据表明AKAP1是Myc的转录靶点，并支持癌细胞的生长。我们鉴定出Sestrin2，一种亮氨酸传感器和雷帕霉素哺乳动物靶点（mTOR）的抑制剂，是AKAP1在线粒体上组装的复合物的一个新组分。AKAP1的下调损害了mTOR途径并抑制了胶质母细胞瘤的生长。AKAP1和Sestrin2的同时缺失逆转了这两种效应。在多种高级别癌症组织中发现了高水平的AKAP1。在肺癌中，AKAP1表达与高水平的Myc、mTOR磷酸化以及患者生存率降低相关。总体而言，这些数据揭示了AKAP1在mTOR途径调节和癌症生长中以前未被认识的作用。线粒体上的AKAP1/mTOR信号整合可能为癌症治疗提供一个新靶点。
