Polson, ES, Kuchler, VB, Abbosh, C et al. (21 more authors) (2017) The small molecule KHS101 induces bioenergetic dysfunction in glioblastoma cells through inhibition of mitochondrial HSPD1. [Preprint - bioRXiv]
Abstract
Pharmacological inhibition of uncontrolled cell growth with small molecule inhibitors is a potential strategy against glioblastoma multiforme (GBM), the most malignant primary brain cancer. Phenotypic profiling of the neurogenic small molecule KHS101 revealed the chemical induction of lethal cellular degradation in molecularly-diverse GBM cells, independent of their tumor subtype, whereas non-cancerous brain cells remained viable. Mechanism-of-action (MOA) studies showed that KHS101 specifically bound and inhibited the mitochondrial chaperone HSPD1. In GBM but not non-cancerous brain cells, KHS101 elicited the aggregation of an enzymatic network that regulates energy metabolism. Compromised glycolysis and oxidative phosphorylation (OXPHOS) resulted in the metabolic energy depletion in KHS101-treated GBM cells. Consistently, KHS101 induced key mitochondrial unfolded protein response factor DDIT3 in vitro and in vivo, and significantly reduced intracranial GBM xenograft tumor growth upon systemic administration, without discernible side effects. These findings suggest targeting of HSPD1-dependent oncometabolic pathways as an anti-GBM therapy.
Metadata
Item Type: | Preprint |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Medicine & Health Faculty Office (Leeds) > Leeds Inst for Data Analytics (LIDA) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number Yorkshire's Brain Tumour Charity was Brain Tumour Res & Support ax Yorks No Ext Ref Given MRC (Medical Research Council) MR/J001171/1 Wellcome Trust 092400/Z/10/Z EU - European Union 303814 Worldwide Cancer Research 13-0146 Cancer Research UK C48431/A18717 Yorkshire's Brain Tumour Charity was Brain Tumour Res & Support ax Yorks No Ext Ref Given Yorkshire's Brain Tumour Charity was Brain Tumour Res & Support ax Yorks N/A |
Depositing User: | Symplectic Publications |
Date Deposited: | 10 Dec 2024 15:00 |
Last Modified: | 10 Dec 2024 15:00 |
Published Version: | https://www.biorxiv.org/content/10.1101/205203v1 |
Identification Number: | 10.1101/205203 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:174624 |