Fasting Improves Therapeutic Response in Hepatocellular Carcinoma Through P53-dependent Metabolic Synergism

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2022 Jan 21

PMID 35061544

Authors

Jelena Krstic

Isabel Reinisch

Katharina Schindlmaier

Markus Galhuber

Zina Riahi

Natascha Berger

Nadja Kupper

Elisabeth Moyschewitz

Martina Auer

Helene Michenthaler

Christoph Nossing

Maria R Depaoli

Jeta Ramadani-Muja

Sinem Usluer

Sarah Stryeck

Martin Pichler

Beate Rinner

Alexander J A Deutsch

Andreas Reinisch

Tobias Madl

Riccardo Zenezini Chiozzi

Albert J R Heck

Meritxell Huch

Roland Malli

Andreas Prokesch

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Current hotspots and trends in cancer metabolic reprogramming: a scientometric analysis.

Yang S, Lin M, Hao S, Ye H, Zhang X Front Immunol. 2024; 15:1497461.

PMID: 39588377 PMC: 11586341. DOI: 10.3389/fimmu.2024.1497461.

Systemic and transcriptional response to intermittent fasting and fasting-mimicking diet in mice.

Michenthaler H, Duszka K, Reinisch I, Galhuber M, Moyschewitz E, Stryeck S BMC Biol. 2024; 22(1):268.

PMID: 39567986 PMC: 11580389. DOI: 10.1186/s12915-024-02061-2.

Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy.

Komza M, Chipuk J J Cell Physiol. 2024; 240(1):e31441.

PMID: 39324415 PMC: 11732733. DOI: 10.1002/jcp.31441.

Alpha lipoic acid diminishes migration and invasion in hepatocellular carcinoma cells through an AMPK-p53 axis.

Hidalgo F, Ferretti A, Etichetti C, Baffo E, Pariani A, Maknis T Sci Rep. 2024; 14(1):21275.

PMID: 39261583 PMC: 11390941. DOI: 10.1038/s41598-024-72309-y.

Suppression of neuronal CDK9/p53/VDAC signaling provides bioenergetic support and improves post-stroke neuropsychiatric outcomes.

Xia J, Zhang T, Sun Y, Huang Z, Shi D, Qin D Cell Mol Life Sci. 2024; 81(1):384.

PMID: 39235466 PMC: 11377386. DOI: 10.1007/s00018-024-05428-4.

References

Grasmann G, Mondal A, Leithner K . Flexibility and Adaptation of Cancer Cells in a Heterogenous Metabolic Microenvironment. Int J Mol Sci. 2021; 22(3). PMC: 7867260. DOI: 10.3390/ijms22031476. View

Shim H, Wei M, Brandhorst S, Longo V . Starvation promotes REV1 SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells. Cancer Res. 2015; 75(6):1056-67. PMC: 4359966. DOI: 10.1158/0008-5472.CAN-14-2249. View

Shi X, Liu J, Ren L, Mao N, Tan F, Ding N . Nutlin-3 downregulates p53 phosphorylation on serine392 and induces apoptosis in hepatocellular carcinoma cells. BMB Rep. 2013; 47(4):221-6. PMC: 4163890. DOI: 10.5483/bmbrep.2014.47.4.146. View

Kastenhuber E, Lowe S . Putting p53 in Context. Cell. 2017; 170(6):1062-1078. PMC: 5743327. DOI: 10.1016/j.cell.2017.08.028. View

Tyanova S, Cox J . Perseus: A Bioinformatics Platform for Integrative Analysis of Proteomics Data in Cancer Research. Methods Mol Biol. 2018; 1711:133-148. DOI: 10.1007/978-1-4939-7493-1_7. View

Fischer M . Census and evaluation of p53 target genes. Oncogene. 2017; 36(28):3943-3956. PMC: 5511239. DOI: 10.1038/onc.2016.502. View

Wheaton W, Weinberg S, Hamanaka R, Soberanes S, Sullivan L, Anso E . Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife. 2014; 3:e02242. PMC: 4017650. DOI: 10.7554/eLife.02242. View

Fischer M, Steiner L, Engeland K . The transcription factor p53: not a repressor, solely an activator. Cell Cycle. 2014; 13(19):3037-58. PMC: 4612452. DOI: 10.4161/15384101.2014.949083. View

Brandhorst S, Choi I, Wei M, Cheng C, Sedrakyan S, Navarrete G . A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015; 22(1):86-99. PMC: 4509734. DOI: 10.1016/j.cmet.2015.05.012. View

10.

Donehower L, Harvey M, Slagle B, McArthur M, Montgomery Jr C, Butel J . Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992; 356(6366):215-21. DOI: 10.1038/356215a0. View

11.

Hopkins B, Pauli C, Du X, Wang D, Li X, Wu D . Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018; 560(7719):499-503. PMC: 6197057. DOI: 10.1038/s41586-018-0343-4. View

12.

Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4):378-90. DOI: 10.1056/NEJMoa0708857. View

13.

Llovet J, Montal R, Sia D, Finn R . Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018; 15(10):599-616. DOI: 10.1038/s41571-018-0073-4. View

14.

Merle P, Blanc J, Phelip J, Pelletier G, Bronowicki J, Touchefeu Y . Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial. Lancet Gastroenterol Hepatol. 2019; 4(6):454-465. DOI: 10.1016/S2468-1253(19)30040-8. View

15.

Pavlova N, Thompson C . The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016; 23(1):27-47. PMC: 4715268. DOI: 10.1016/j.cmet.2015.12.006. View

16.

DeWaal D, Nogueira V, Terry A, Patra K, Jeon S, Guzman G . Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 2018; 9(1):446. PMC: 5792493. DOI: 10.1038/s41467-017-02733-4. View

17.

Vasan K, Werner M, Chandel N . Mitochondrial Metabolism as a Target for Cancer Therapy. Cell Metab. 2020; 32(3):341-352. PMC: 7483781. DOI: 10.1016/j.cmet.2020.06.019. View

18.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

19.

Stryeck S, Gastrager M, Degoricija V, Trbusic M, Potocnjak I, Radulovic B . Serum Concentrations of Citrate, Tyrosine, 2- and 3- Hydroxybutyrate are Associated with Increased 3-Month Mortality in Acute Heart Failure Patients. Sci Rep. 2019; 9(1):6743. PMC: 6494857. DOI: 10.1038/s41598-019-42937-w. View

20.

Fiume L, Vettraino M, Manerba M, Di Stefano G . Inhibition of lactic dehydrogenase as a way to increase the anti-proliferative effect of multi-targeted kinase inhibitors. Pharmacol Res. 2010; 63(4):328-34. DOI: 10.1016/j.phrs.2010.12.005. View