Inhibition of anti-apoptotic Bcl-2 family members promotes synergistic cell death with ER stress inducers by disrupting autophagy in glioblastoma

Glioblastoma (GBM) remains one of the most aggressive and challenging brain tumors. Unfortunately, current clinical treatment options offer limited efficacy, highlighting the necessity for uncovering novel therapeutic strategies. Here, monotherapy and combination library screening were employed, and identified that the efficacy of obatoclax, a pan-Bcl-2 family inhibitor, was improved significantly when combined with ER-stress inducers, including tunicamycin. Combinatorial knockdown of anti-apoptotic proteins confirmed that the loss of Mcl-1 and Bcl-xL synergistically enhanced apoptosis under ER stress conditions. Although ER stress inducers triggered the stress response in GBM cells, obatoclax co-treatment enhanced this response by upregulating ATF-4 and CHOP, which promoted apoptosis along with increased caspase 3/7 activity and cleavage of PARP. ATF-4 knockdown significantly decreased the apoptosis induced by obatoclax and tunicamycin co-treatment and reduced the expression of CHOP and BIM. Under ER stress responses, GBM cells exerted an autophagy response to recover from the stress condition; however, obatoclax co-treatment disrupted the autophagy responses, particularly by disrupting autophagic cargo degradation. Our findings suggest that targeting Mcl-1 and Bcl-xL, coupled with ER-stress induction, could be a promising strategy for the treatment of GBM, highlighting the potential for combination therapies involving pan-Bcl-2 family inhibitors to overcome current limitations in the treatment of GBM.