The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma

Ozyerli-Goknar, Ezgi and Sur-Erdem, Ilknur and Seker, Fidan and Cingöz, Ahmet and Kayabolen, Alisan and Kahya-Yesil, Zeynep and Uyulur, Fırat and Gezen, Melike and Tolay, Nazife and Erman, Batu and Gönen, Mehmet and Dunford, James and Oppermann, Udo and Bagci-Onder, Tugba (2019) The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma. Cell Death and Disease, 10 . ISSN 2041-4889

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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.
Item Type: Article
Divisions: Faculty of Engineering and Natural Sciences > Academic programs > Biological Sciences & Bio Eng.
Faculty of Engineering and Natural Sciences
Depositing User: Batu Erman
Date Deposited: 28 Jul 2023 20:22
Last Modified: 28 Jul 2023 20:22

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