The small molecule KHS101 induces bioenergetic dysfunction in glioblastoma cells through inhibition of mitochondrial HSPD1
- 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.
- Authors:
- E Polson, V Kuchler, C Abbosh, E Ross, R Mathew, H Beard, E Chuntharpursat-Bon, J Williams, BD Silva, H Shao, A Patel, A Davies, A Droop, HBS Griffiths, P Chumas, S Short, M Lorger, J Gestwicki, L Roberts, R Bon, S Allison, S Zhu, F Markowetz, H Wurdak
- Publication date:
- 1st Aug 2017
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- DOI