Fasting improves therapeutic response in hepatocellular carcinoma through p53-dependent metabolic synergism.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
21 Jan 2022
21 Jan 2022
Historique:
entrez:
21
1
2022
pubmed:
22
1
2022
medline:
22
1
2022
Statut:
ppublish
Résumé
Cancer cells voraciously consume nutrients to support their growth, exposing metabolic vulnerabilities that can be therapeutically exploited. Here, we show in hepatocellular carcinoma (HCC) cells, xenografts, and patient-derived organoids that fasting improves sorafenib efficacy and acts synergistically to sensitize sorafenib-resistant HCC. Mechanistically, sorafenib acts noncanonically as an inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded AKT/mTOR signaling, prevents this Warburg shift. Regulating glucose transporter and proapoptotic protein expression, p53 is necessary and sufficient for the sorafenib-sensitizing effect of fasting. p53 is also crucial for fasting-mediated improvement of sorafenib efficacy in an orthotopic HCC mouse model. Together, our data suggest fasting and sorafenib as rational combination therapy for HCC with intact p53 signaling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies aimed at improving therapy response in advanced-stage HCC.
Identifiants
pubmed: 35061544
doi: 10.1126/sciadv.abh2635
pmc: PMC8782451
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
eabh2635Subventions
Organisme : Austrian Science Fund FWF
ID : DOC 31
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : I 3165
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : W 1226
Pays : Austria
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