1. Mitochondrial AKAP1 supports mTOR pathway and tumor growth
- Author
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Rinaldi L., Sepe M., Delle Donne R., Conte K., Arcella A., Borzacchiello D., Amente S., De Vita F., Porpora M., Garbi C., Oliva M. A., Procaccini C., Faicchia D., Matarese G., Zito Marino F., Rocco G., Pignatiello S., Franco R., Insabato L., Majello B., Feliciello A., ZITO MARINO, Federica, Rinaldi, L., Sepe, M., Delle Donne, R., Conte, K., Arcella, A., Borzacchiello, D., Amente, S., De Vita, F., Porpora, M., Garbi, C., Oliva, M. A., Procaccini, C., Faicchia, D., Matarese, G., Zito Marino, F., Rocco, G., Pignatiello, S., Franco, R., Insabato, L., Majello, B., Feliciello, A., ZITO MARINO, Federica, 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, and Feliciello, Antonio
- Subjects
0301 basic medicine ,Scaffold protein ,Male ,Cancer Research ,Lung Neoplasms ,Transcription, Genetic ,A Kinase Anchor Proteins ,Mitochondrion ,mTORC2 ,RNA, Small Interfering ,Nuclear Protein ,Mitochondrial ,AKAP1 ,mTOR ,TOR Serine-Threonine Kinase ,Brain Neoplasms ,TOR Serine-Threonine Kinases ,Nuclear Proteins ,A Kinase Anchor Protein ,3. Good health ,Cell biology ,Mitochondria ,Gene Expression Regulation, Neoplastic ,Original Article ,Survival Analysi ,Signal transduction ,Neuroglia ,Protein Binding ,Signal Transduction ,Immunology ,Mice, Nude ,Biology ,Brain Neoplasm ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Cell Line, Tumor ,Animals ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Epithelial Cell ,Cell growth ,Animal ,RPTOR ,Epithelial Cells ,Cell Biology ,Survival Analysis ,Lung Neoplasm ,030104 developmental biology ,Cancer research ,Organelle biogenesis ,Neoplasm Transplantation - Abstract
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.
- Published
- 2017
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