Mitochondrial AKAP1 supports mTOR pathway and tumor growth

• Published in: Cell death & disease 2017-06, Vol.8 (6), p.e2842-e2842
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 631/67/1059; 631/67/1922; 631/80/458/1733; 631/80/86; A Kinase Anchor Proteins - antagonists & inhibitors; A Kinase Anchor Proteins - genetics; A Kinase Anchor Proteins - metabolism; Animals; Antibodies; Biochemistry; Bioenergetics; Biomedical and Life Sciences; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cancer; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Proliferation; Cell survival; Cyclic AMP; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene Expression Regulation, Neoplastic; Glioblastoma; Immunology; Integration; Leucine; Life Sciences; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Metabolism; Mice, Nude; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Myc protein; Neoplasm Transplantation; Neuroglia - metabolism; Neuroglia - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nutrient availability; Original; original-article; Oxidative metabolism; Phosphorylation; Protein Binding; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Rapamycin; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Src protein; Survival; Survival Analysis; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription; Transcription, Genetic; Tumorigenesis
• ISSN: 2041-4889; 2041-4889
• 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.