Abstract
Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- and radio-therapy, a currently poor prognosis of GBM patients highlights an urgent need for novel treatment strategies. TRAIL (TNF Related Apoptosis Inducing Ligand) is a potent anti-cancer agent that can induce apoptosis selectively in cancer cells. GBM cells frequently develop resistance to TRAIL which renders clinical application of TRAIL therapeutics inefficient. In this study, we undertook a chemical screening approach using a library of epigenetic modifier drugs to identify compounds that could augment TRAIL response. We identified the fungal metabolite chaetocin, an inhibitor of histone methyl transferase SUV39H1, as a novel TRAIL sensitizer. Combining low subtoxic doses of chaetocin and TRAIL resulted in very potent and rapid apoptosis of GBM cells. Chaetocin also effectively sensitized GBM cells to further pro-apoptotic agents, such as FasL and BH3 mimetics. Chaetocin mediated apoptosis sensitization was achieved through ROS generation and consequent DNA damage induction that involved P53 activity. Chaetocin induced transcriptomic changes showed induction of antioxidant defense mechanisms and DNA damage response pathways. Heme Oxygenase 1 (HMOX1) was among the top upregulated genes, whose induction was ROS-dependent and HMOX1 depletion enhanced chaetocin mediated TRAIL sensitization. Finally, chaetocin and TRAIL combination treatment revealed efficacy in vivo. Taken together, our results provide a novel role for chaetocin as an apoptosis priming agent and its combination with pro-apoptotic therapies might offer new therapeutic approaches for GBMs.
Highlights
Glioblastoma multiforme (GBM) is grade IV glioma[1] that represents >45% of primary brain tumors with an incidence of 3.2/100,000 per year[2]
While SAHA, a wellknown histone deacetylase (HDAC) inhibitor, has been previously reported to cooperate with TRAIL41 and the antitumor role of protein kinase HASPIN has been established[42,43], chaetocin has not been studied in relation to tumor necrosis factor-related apoptosisinducing ligand (TRAIL) in GBM
In this study, we interrogated the effects of epigenetic modifying compounds on GBM cell apoptosis in a screening approach and identified chaetocin as a novel sensitizer for apoptotic therapies in GBM cells
Summary
Glioblastoma multiforme (GBM) is grade IV glioma[1] that represents >45% of primary brain tumors with an incidence of 3.2/100,000 per year[2]. Despite recent therapeutic developments[3], the median survival for GBM patients is 14.6 months, and only a small fraction of patients (3%) live. One therapeutic strategy is to selectively induce cancer cell death. Apoptosis is a programmed cellular selfdestruction process[6], which fosters the maintenance of tissue homeostasis through elimination of pre-malignant cells, it is a barrier for cancer progression. Apoptosis can be triggered extrinsically with proapoptotic ligands, such as tumor necrosis factor-related apoptosisinducing ligand (TRAIL)[7] that utilize the death receptors (DR4/DR5), Death Inducing Signaling Complex (DISC) and initiator caspases (caspases 8 and 10)[8]. Intrinsic apoptosis is activated via DNA damaging drugs[9] or other agents, such as BH3 mimetics[10], which involves mitochondrial outer membrane permeabilization via BAK or Official journal of the Cell Death Differentiation Association
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