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Activation of the Mitochondrial ClpP protease is Synthetically Lethal with HDAC1/2 Inhibition in Glioblastoma Model Systems

ABSTRACT: By integration of transcriptome and metabolite analyses, we showed that pharmacological activation of the mitochondrial ClpP protease through utilization of enhanced imipridone compounds (ONC206 and ONC212) in combination with global (Panobinostat) and selective (romidepsin) HDAC – inhibitors caused synergistic reduction of viability in established and patient-derived xenograft (PDX) cultures of human GBM. This effect occurred independent of TP53 status and was partially mediated by activation of a cell death with apoptotic features accompanied by activation of initiator and effector caspases as well as cleavage of PARP. Consistently, the combination treatment altered the expression of anti-apoptotic and pro-apoptotic Bcl-2 family members, resulting in down-regulation of Bcl-xL and Mcl-1. Knockdown experiments targeting Noxa, BIM, Bcl-xL and Mcl-1 confirmed a functional implication of these proteins in the reduction of cellular viability mediated by the combination treatment. Importantly, knockdown of the ClpP protease significantly rescued the reduction of cellular viability by ClpP activators and the combination treatment, respectively, suggesting critical involvement of this protein. We used microarrays to detail the global programme of gene expression underlying cellularization and identified distinct classes of up-regulated and down-regulated genes in cells treated with ONC206 and Romidepsin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166111 | GEO | 2022/01/24

REPOSITORIES: GEO

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Activation of the Mitochondrial ClpP protease is Synthetically Lethal with HDAC1/2 Inhibition in Glioblastoma Model Systems

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