Fasting improves therapeutic response in hepatocellular carcinoma through p53-dependent metabolic synergism
Krstic, Jelena; Reinisch, Isabel; Schindlmaier, Katharina; Galhuber, Markus; Riahi, Zina; Berger, Natascha; Kupper, Nadja; Moyschewitz, Elisabeth; Auer, Martina; Michenthaler, Helene; Nössing, Christoph; Depaoli, Maria R; Ramadani-Muja, Jeta; Usluer, Sinem; Stryeck, Sarah; Pichler, Martin; Rinner, Beate; Deutsch, Alexander J A; Reinisch, Andreas; Madl, Tobias; Chiozzi, Riccardo Zenezini; Heck, Albert J R; Huch, Meritxell; Malli, Roland; Prokesch, Andreas
(2022) Science advances, volume 8, issue 3, pp. 1 - 19
(Article)
Abstract
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
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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.
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Keywords: General
ISSN: 2375-2548
Publisher: American Association for the Advancement of Science
Note: Funding Information: J.K. was funded and supported by the Austrian Science Fund (FWF, grant P29328), by a grant of the Oesterreichische Nationalbank (Austrian Central Bank, Anniversary Fund, project number 18517), and by a MEFOgraz research grant. I.R. was funded by the PhD faculty MolMed at the Medical University of Graz. I.R., M.G., K.S., N.B., N.K., H.M., and C.N. were supported by the Austrian Science Fund (FWF, grants P29328 and I3165). A.P. was supported by the Austrian Science Fund (FWF, grants P29328, P34109, and I3165) and by a MEFOgraz grant from the Medical University of Graz. This work has also been supported by EPIC-XS (0000260), funded by the Horizon 2020 program of the European Union. T.M. was supported by the Austrian Science Foundation grants P28854, I3792, and DK-MCD W1226; Austrian Research Promotion Agency (FFG) grants 864690 and 870454; the Integrative Metabolism Research Center Graz; and Austrian Infrastructure Program 2016/2017, the Styrian Government (Zukunftsfonds), and BioTechMed-Graz (Flagship project). S.S., M.G., N.B., and N.K. were trained within the frame of the PhD program Molecular Medicine, Medical University of Graz. Publisher Copyright: Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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