Mitochondrial AKAP1 supports mTOR pathway and tumor growth
#MMPMID28569781
Rinaldi L
; Sepe M
; Delle Donne R
; Conte K
; Arcella A
; Borzacchiello D
; Amente S
; De Vita F
; Porpora M
; Garbi C
; Oliva MA
; Procaccini C
; Faicchia D
; Matarese G
; Zito Marino F
; Rocco G
; Pignatiello S
; Franco R
; Insabato L
; Majello B
; Feliciello A
Cell Death Dis
2017[Jun]; 8
(6
): e2842
PMID28569781
show ga
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.
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