Reversing the HDAC-inhibitor mediated metabolic escape in MYCN-amplified neuroblastoma - 27/05/22
Abstract |
In MYCN-amplified neuroblastoma (NB), we noticed that the single compound treatment with the HDAC inhibitor vorinostat led to a reprogramming of the glycolytic pathway in these cells. This reprogramming was upregulation of fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS), allowing the cells to generate ATP, albeit at a reduced rate. This behavior was dependent on reduced levels of MYCN and a corresponding increase in the levels of PPARD transcription factors. By integrating metabolic and functional studies in NB cells and mouse xenografts, we demonstrate a compensatory upregulation of FAO/OXPHOS metabolism that promotes resistance to HDAC inhibitors. From the additional compounds that could reverse this metabolic reprogramming, the mTORC1 inhibitor sirolimus was selected. Besides both a block of glycolysis and OXPHOS, the HDAC/mTORC1 inhibitor combination produced significantly higher levels of reactive oxygen species (ROS) in the treated cells and in xenograft tumor samples, also a consequence of increased glycolytic block. The lead compounds were also tested for changes in the message levels of the glycolytic enzymes and their pathway activity, and HK2 and GPI glycolytic enzymes were most affected at their RNA message level. This combination was seen with no overall toxicity in treated mice in terms of weight loss or liver/kidney function.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Glycolysis screen of therapeutic compounds potentiating HDAC inhibitor block. |
• | mTORC1 inhibitor prevented elevated oxidative phosphorylation due to HDAC inhibitor. |
• | Combination compounds produced high levels of cytotoxic ROS in xenograft tumors. |
• | With dual pathway inhibition, no observed toxicity was seen in treated mice. |
Abbreviations : ACADSB, ACADVL, ALDOA, CHOP, DMSO, ENO1, FAO, GAPDH, GPI, H&E, HADHB, HDAC, HDACI, HK2, Ki67, LDHA, mTORC1, NB, OXPHOS, PARP, PDI, PFKL, PGAM1, PGK1, PKM2, PPARD, PYR
Keywords : Glycolysis, Neuroblastoma, Sirolimus, Vorinostat, Warburg effect
Plan
Vol 150
Article 113032- juin 2022 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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