Myc-mediated transcriptional regulation of the mitochondrial chaperone TRAP1 controls primary and metastatic tumor growth.
Animals
Cell Line, Tumor
Cell Movement
Cell Survival
/ drug effects
Guanidines
/ pharmacology
HSP90 Heat-Shock Proteins
/ genetics
Humans
Lactams, Macrocyclic
/ pharmacology
Liver Neoplasms
/ drug therapy
Male
Membrane Potential, Mitochondrial
/ drug effects
Mice
Mice, Nude
Mitochondria
/ metabolism
Oxidative Phosphorylation
Promoter Regions, Genetic
Prostatic Neoplasms
/ drug therapy
Proto-Oncogene Proteins c-myc
/ antagonists & inhibitors
RNA Interference
RNA, Small Interfering
/ metabolism
Transcription, Genetic
Myc (c-Myc)
TRAP1
invasion
metabolism
metastasis
mitochondria
oxidative phosphorylation
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
05 07 2019
05 07 2019
Historique:
received:
28
03
2019
revised:
08
05
2019
pubmed:
18
5
2019
medline:
11
3
2020
entrez:
18
5
2019
Statut:
ppublish
Résumé
The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown. Using a variety of cancer cell lines and several technical approaches, including siRNA-mediated gene silencing, ChIP assays, global metabolomics and focused metabolite analyses, bioenergetics, and cell viability assays, we show that two oncogenic Myc proteins, c-Myc and N-Myc, transcriptionally control the expression of the mitochondrial chaperone TNFR-associated protein-1 (TRAP1) in cancer. In turn, this Myc-mediated regulation preserved the folding and function of mitochondrial oxidative phosphorylation (OXPHOS) complex II and IV subunits, dampened reactive oxygen species production, and enabled oxidative bioenergetics in tumor cells. Of note, we found that genetic or pharmacological targeting of this pathway shuts off tumor cell motility and invasion, kills Myc-expressing cells in a TRAP1-dependent manner, and suppresses primary and metastatic tumor growth
Identifiants
pubmed: 31097545
pii: S0021-9258(20)31834-2
doi: 10.1074/jbc.AC119.008656
pmc: PMC6615691
doi:
Substances chimiques
Guanidines
0
HSP90 Heat-Shock Proteins
0
Lactams, Macrocyclic
0
Proto-Oncogene Proteins c-myc
0
RNA, Small Interfering
0
TRAP1 protein, human
0
gamitrinib-G4
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
10407-10414Subventions
Organisme : NCI NIH HHS
ID : P01 CA140043
Pays : United States
Organisme : NIH HHS
ID : S10 OD023586
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211199
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA224769
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA051497
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA220446
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA204593
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221838
Pays : United States
Informations de copyright
© 2019 Agarwal et al.
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