UMI-77 primes glioma cells for TRAIL-induced apoptosis by unsequestering Bim and Bak from Mcl-1.
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.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.
Ji-Wei
JW
Liu
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China. dontyousee@163.com.
Zhi-Chuan
ZC
Zhu
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China.
Kui
K
Li
School of Life Science and Technology, Xinxiang Medical University, Henan, 453003, People's Republic of China.
Hong-Tao
HT
Wang
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.
Zhi-Qi
ZQ
Xiong
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, People's Republic of China. zhengjing@ecust.edu.cn.
Jing
J
Zheng
D017209:Apoptosis / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013864:Thioglycolates / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
C494772:BAK1 protein, human; D000072224:Bcl-2-Like Protein 11; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D013864:Thioglycolates; C000592878:UMI-77; D050998:bcl-2 Homologous Antagonist-Killer Protein
Malignant glioma; Mcl-1; TRAIL; UMI-77