Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance.
ATP-Binding Cassette Transporters
/ metabolism
Adenosine Triphosphate
/ metabolism
Animals
Antineoplastic Agents
/ pharmacokinetics
Biomimetic Materials
/ chemistry
Cell Line, Tumor
Cell Respiration
/ drug effects
Doxorubicin
/ pharmacokinetics
Drug Resistance, Multiple
/ physiology
Drug Resistance, Neoplasm
/ physiology
Female
HSP40 Heat-Shock Proteins
/ deficiency
Humans
In Vitro Techniques
Mice
Mice, Inbred NOD
Mice, SCID
Mitochondria
/ drug effects
Neoplasms
/ drug therapy
Oxygen Consumption
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 05 2021
14 05 2021
Historique:
received:
01
10
2020
accepted:
12
04
2021
entrez:
15
5
2021
pubmed:
16
5
2021
medline:
4
6
2021
Statut:
epublish
Résumé
Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers.
Identifiants
pubmed: 33990571
doi: 10.1038/s41467-021-23071-6
pii: 10.1038/s41467-021-23071-6
pmc: PMC8121950
doi:
Substances chimiques
ATP-Binding Cassette Transporters
0
Antineoplastic Agents
0
DNAJC15 protein, human
0
HSP40 Heat-Shock Proteins
0
Doxorubicin
80168379AG
Adenosine Triphosphate
8L70Q75FXE
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2804Subventions
Organisme : NCI NIH HHS
ID : R21 CA223389
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116073
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI055402
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA127099
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103496
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS048154
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI110016
Pays : United States
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