Abstract 12P
Background
Glioblastoma (GBM) is the most aggressive tumour originating from the brain. At present, surgery combined with radiotherapy and chemotherapy is the main therapy modality for GBM. However, the prognosis for patients with GBM still remains poor. It is known that malignant glioblastoma cells are more susceptible to unfolded protein response (UPR) and ERs because of high level of protein synthesis. Therefore, the potential vulnerability of the ER in GBM cells via the disturbance of UPR may hold therapeutic promise for GBM.
Methods
We isolated a class of aspergin derivatives from Eurotium cristatum through polyketide synthase (PKS) and phosphatase (PTase)-dependent genome mining-aided biosynthesis. A methodology was developed to screen anti-glioma compounds in primary culture cells as well as Temozolomide (TMZ)-resistant ERs-sensitive cells. Apoptotic ability of decitabine (DAC) was tested by electron microscopy. Confocal scanning was performed to investigate the DAC-induced UPR and harmful autophagy in ER. Seahorse Mito-Stress test and electron transport chain (ETC) activity assay were used to evaluate the oxygen consumption rate, ATP production, and OXPHOS effect of DAC-treated cells. Xenograft mouse models was established to confirm the anti-glioma effect of DAC on tumour growth.
Results
Firstly, the data indicated that DAC induced dysfunction of ER-mitochondria communication as well as ERs-dependent apoptosis via disrupting the mitochondrion-associated ER membrane (MAM) machinery. Secondly, it was demonstrated that DAC blocked degradation of PACS2 resulting in over-link of MAM networks and destabilization of the ER-mitochondria crosstalk. Thirdly, accumulation of PACS2 promoted translocation of Bid to mitochondria, thereby facilitating disturbances in OXPHOS-dependent energy metabolism. Furthermore, we observed high cIAP1 and low PACS2 expression levels in glioma tissues, Finally, it was confirmed that DAC-induced suppression of PACS2 degradation contributed to anti-glioma activity in vivo.
Conclusions
In conclusion, these findings suggested that DAC might be a candidate for the treatment of ERs-sensitive malignant gliomas through negatively regulating cIAP-mediated degradation of PACS2. Moreover, our study provides new insights that ER-mitochondria contact sites might be therapeutic targets of GBM.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.