Huang Tianyi, Takagi Satoshi, Koike Sumie, Katayama Ryohei
Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, Japan.
Cell Death Discov. 2025 Jul 24;11(1):340. doi: 10.1038/s41420-025-02632-4.
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.
胶质母细胞瘤（GBM）仍然是最具侵袭性和挑战性的脑肿瘤之一。不幸的是，目前的临床治疗选择疗效有限，这凸显了探索新治疗策略的必要性。在此，采用了单药治疗和组合文库筛选，发现泛Bcl-2家族抑制剂奥巴托克斯与包括衣霉素在内的内质网应激诱导剂联合使用时，疗效显著提高。抗凋亡蛋白的组合敲低证实，在应激条件下，Mcl-1和Bcl-xL的缺失协同增强了细胞凋亡。虽然内质网应激诱导剂引发了GBM细胞中的应激反应，但奥巴托克斯联合治疗通过上调ATF-4和CHOP增强了这种反应，这促进了细胞凋亡，同时增加了caspase 3/7活性和PARP的裂解。ATF-4敲低显著降低了奥巴托克斯和衣霉素联合治疗诱导的细胞凋亡，并降低了CHOP和BIM的表达。在内质网应激反应下，GBM细胞发挥自噬反应以从应激状态中恢复；然而，奥巴托克斯联合治疗破坏了自噬反应，特别是通过破坏自噬货物降解。我们的研究结果表明，靶向Mcl-1和Bcl-xL，结合内质网应激诱导，可能是治疗GBM的一种有前景的策略，凸显了涉及泛Bcl-2家族抑制剂的联合疗法克服当前GBM治疗局限性的潜力。
