Abstract 3774: The effect of CDK5 on mitochondrial function in Glioblastoma Multiforme (GBM)

Abstract

Abstract Glioblastoma Multiforme (GBM) is the most common and aggressive form of brain tumors.Despite conventional therapies, average patient survival is less than two years. GBMrecurrence is in part due to self-renewing tumor initiating cells, often called glioma stemcells (GSCs), which are characterized by their proliferation and tumor formation capacity,as well as their metabolic features. Thus, mitochondrial function represents a potentiallink between cellular metabolism and differentiation state. Mitochondrial fission isindispensable for growing and dividing cells. Dynamin-related protein 1 (Drp1) is essentialfor this process. In particular, there is cumulative evidence that links Drp1 with severaltypes of cancers, including GBM. Regulation of Drp1 is mainly controlled by post-translational modifications (PTMs). Importantly, recent studies have shown CDK5-dependent phosphorylation at the activating site serine 616 of Drp1 enhancesmitochondrial fission. CDK5 plays a crucial role in the central nervous system as well as,in tumor progression. Therefore, our lab hypothesized that inhibition of CDK5 would targetmitochondrial function in order to decrease tumor growth and sensitize brain tumors toconventional therapies. Western blot analysis has shown that CDK5-dependentphosphorylation of Drp1 is present in GSCs and GBM cell lines but absent in non-stemtumor cells (NSTC) and astrocytes. Small-molecule CDK5 inhibitors or CDK5 knockdownthrough siRNA in GSCs and GBM cell lines decreased activating phosphorylation of Drp1,leading to elongation of mitochondria morphology and corresponding reductions in cellviability and cell proliferation. Additionally, CDK5 inhibition showed sensitization toionizing radiation (IR) in GSCs and GBM cells. Importantly, CDK5 inhibition or knockdowncombined with IR, showed increased levels of cleaved caspase-7 and cleaved PARPsuggesting a role for apoptosis in decreased cell proliferation and sensitization to IR.Interestingly, CDK5 inhibition also diminished mitochondrial oxidative phosphorylation.Overall, these findings highlight an important role for CDK5 in regulating mitochondrialfunction in GBM, and targeting CDK5 offers a novel strategy to sensitize tumors to chemo-and radiotherapies. Citation Format: Adina Brett-Morris, Jason Mears, Kristy Rochon. The effect of CDK5 on mitochondrial function in Glioblastoma Multiforme (GBM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3774.