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UMI-77 primes glioma cells for TRAIL-induced apoptosis by unsequestering Bim and Bak from Mcl-1
Ji-Wei Liu1, Zhi-Chuan Zhu2, Kui Li3
1Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.
Abstract:
Malignant glioma is the most common and aggressive form of brain tumor with poor prognosis of survival. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent but is insufficient of inducing apoptosis in some types of gliomas. In this study, we showed that the small-molecule Mcl-1 inhibitor UMI-77 sensitized glioma cells to TRAIL treatment, as evidenced by cell viability assay, Annexin V staining and JC-1 staining. Combination of UMI-77 and TRAIL in glioma cells led to the activation of caspase-8 and Bid, cleavage of caspase-3 and poly-ADP ribose polymerase (PARP), accumulation of tBid in the mitochondria and release of cytochrome c into the cytosol. UMI-77 alone or in combination with TRAIL untethered pro-apoptotic Bcl-2 proteins Bim and Bak from the sequestration of Mcl-1 and promoted the conformational activation of Bak. Small hairpin RNA (shRNA) of Bid attenuated the cleavage of caspase-8, Bid, caspase-3 and PARP, and reduced the cytotoxicity of UMI-77 plus TRAIL as compared with control shRNA cells, indicating this synergy entails the crosstalk between extrinsic and intrinsic apoptotic signaling. Taken together, UMI-77 enhances TRAIL-induced apoptosis by unsequestering Bim and Bak, which provides a novel therapeutic strategy for the treatment of gliomas.
Insights
The Mcl-1 inhibitor UMI-77 sensitizes malignant glioma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy. This combination enhances apoptosis by releasing key proteins, offering a new treatment strategy for gliomas.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Malignant glioma is an aggressive brain tumor with limited treatment options.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows potential but is ineffective in some gliomas.
Purpose of the Study:
- To investigate if the small-molecule Mcl-1 inhibitor UMI-77 can sensitize glioma cells to TRAIL treatment.
- To elucidate the molecular mechanisms underlying the combined effect of UMI-77 and TRAIL.
Main Methods:
- Cell viability assays, Annexin V, and JC-1 staining were used to assess apoptosis.
- Western blotting and mitochondrial assays were performed to analyze apoptotic pathway activation.
- Small hairpin RNA (shRNA) targeting Bid was used to investigate the role of this protein.
Main Results:
- UMI-77 sensitized glioma cells to TRAIL, increasing apoptosis.
- The combination activated caspase-8 and Bid, leading to caspase-3 and PARP cleavage.
- UMI-77 released Bim and Bak from Mcl-1, promoting Bak activation and cytochrome c release.
- Bid knockdown reduced the synergistic cytotoxicity, indicating crosstalk between extrinsic and intrinsic apoptotic pathways.
Conclusions:
- UMI-77 enhances TRAIL-induced apoptosis in glioma cells by modulating Mcl-1 and apoptotic proteins.
- This combination therapy represents a novel therapeutic strategy for malignant gliomas.
