PMID- 28569781
OWN - NLM
STAT- MEDLINE
DCOM- 20180306
LR  - 20211204
IS  - 2041-4889 (Electronic)
VI  - 8
IP  - 6
DP  - 2017 Jun 1
TI  - Mitochondrial AKAP1 supports mTOR pathway and tumor growth.
PG  - e2842
LID - 10.1038/cddis.2017.241 [doi]
AB  - 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.
FAU - Rinaldi, Laura
AU  - Rinaldi L
AD  - Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, 
      University Federico II, Naples, Italy.
FAU - Sepe, Maria
AU  - Sepe M
AD  - Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, 
      University Federico II, Naples, Italy.
FAU - Delle Donne, Rossella
AU  - Delle Donne R
AD  - Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, 
      University Federico II, Naples, Italy.
FAU - Conte, Kristel
AU  - Conte K
AD  - Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, 
      University Federico II, Naples, Italy.
FAU - Arcella, Antonietta
AU  - Arcella A
AD  - I.R.C.C.S Neuromed, Pozzilli, Italy.
FAU - Borzacchiello, Domenica
AU  - Borzacchiello D
AD  - I.R.G.S., Biogem, Ariano Irpino, Avellino, Italy.
FAU - Amente, Stefano
AU  - Amente S
AD  - Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, 
      University Federico II, Naples, Italy.
FAU - De Vita, Fernanda
AU  - De Vita F
AD  - I.R.G.S., Biogem, Ariano Irpino, Avellino, Italy.
FAU - Porpora, Monia
AU  - Porpora M
AD  - Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, 
      University Federico II, Naples, Italy.
FAU - Garbi, Corrado
AU  - Garbi C
AD  - Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, 
      University Federico II, Naples, Italy.
FAU - Oliva, Maria A
AU  - Oliva MA
AD  - I.R.C.C.S Neuromed, Pozzilli, Italy.
FAU - Procaccini, Claudio
AU  - Procaccini C
AD  - Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, 
      University Federico II, Naples, Italy.
FAU - Faicchia, Deriggio
AU  - Faicchia D
AD  - Department of Translational Medical Sciences, University Federico II, Naples, 
      Italy.
FAU - Matarese, Giuseppe
AU  - Matarese G
AD  - Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, 
      University Federico II, Naples, Italy.
FAU - Zito Marino, Federica
AU  - Zito Marino F
AD  - Pathology Unit, Naples, National Cancer Institute, Fondazione Pascale, Naples, 
      Italy.
FAU - Rocco, Gaetano
AU  - Rocco G
AD  - Division of Thoracic Surgery, National Cancer Institute, Fondazione Pascale, 
      Naples, Italy.
FAU - Pignatiello, Sara
AU  - Pignatiello S
AD  - Department of Advanced Biomedical Sciences, University Federico II, Naples, 
      Italy.
FAU - Franco, Renato
AU  - Franco R
AD  - Pathology Unit, Naples, National Cancer Institute, Fondazione Pascale, Naples, 
      Italy.
AD  - Department of Mental and Physical Health and Preventive Medicine, Second 
      University of Naples, Naples, Italy.
FAU - Insabato, Luigi
AU  - Insabato L
AD  - Department of Advanced Biomedical Sciences, University Federico II, Naples, 
      Italy.
FAU - Majello, Barbara
AU  - Majello B
AD  - Department of Biology, University Federico II, Naples, Italy.
FAU - Feliciello, Antonio
AU  - Feliciello A
AD  - Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, 
      University Federico II, Naples, Italy.
LA  - eng
PT  - Journal Article
DEP - 20170601
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (A Kinase Anchor Proteins)
RN  - 0 (AKAP1 protein, human)
RN  - 0 (MYC protein, human)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (SESN2 protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - A Kinase Anchor Proteins/antagonists & inhibitors/*genetics/metabolism
MH  - Animals
MH  - Brain Neoplasms/*genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Epithelial Cells/metabolism/pathology
MH  - *Gene Expression Regulation, Neoplastic
MH  - Lung Neoplasms/*genetics/metabolism/mortality/pathology
MH  - Male
MH  - Mice, Nude
MH  - Mitochondria/*genetics/metabolism
MH  - Neoplasm Transplantation
MH  - Neuroglia/metabolism/pathology
MH  - Nuclear Proteins/genetics/metabolism
MH  - Protein Binding
MH  - Proto-Oncogene Proteins c-myc/*genetics/metabolism
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Signal Transduction
MH  - Survival Analysis
MH  - TOR Serine-Threonine Kinases/*genetics/metabolism
MH  - Transcription, Genetic
PMC - PMC5520900
COIS- The authors declare no conflict of interest.
EDAT- 2017/06/02 06:00
MHDA- 2018/03/07 06:00
PMCR- 2017/06/01
CRDT- 2017/06/02 06:00
PHST- 2016/12/05 00:00 [received]
PHST- 2017/04/06 00:00 [revised]
PHST- 2017/04/28 00:00 [accepted]
PHST- 2017/06/02 06:00 [entrez]
PHST- 2017/06/02 06:00 [pubmed]
PHST- 2018/03/07 06:00 [medline]
PHST- 2017/06/01 00:00 [pmc-release]
AID - cddis2017241 [pii]
AID - 10.1038/cddis.2017.241 [doi]
PST - epublish
SO  - Cell Death Dis. 2017 Jun 1;8(6):e2842. doi: 10.1038/cddis.2017.241.