Liu Ji-Wei, Zhu Zhi-Chuan, Li Kui, Wang Hong-Tao, Xiong Zhi-Qi, Zheng Jing
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.
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.
Mol Cell Biochem. 2017 Aug;432(1-2):55-65. doi: 10.1007/s11010-017-2997-x. Epub 2017 Mar 23.
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.
恶性胶质瘤是最常见且侵袭性最强的脑肿瘤形式，生存预后较差。肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种有前景的抗癌药物，但在某些类型的胶质瘤中诱导凋亡的能力不足。在本研究中，我们发现小分子Mcl-1抑制剂UMI-77使胶质瘤细胞对TRAIL治疗敏感，细胞活力测定、膜联蛋白V染色和JC-1染色证明了这一点。UMI-77与TRAIL联合作用于胶质瘤细胞导致半胱天冬酶-8和Bid活化、半胱天冬酶-3和聚ADP核糖聚合酶（PARP）裂解、tBid在线粒体中积累以及细胞色素c释放到细胞质中。单独的UMI-77或与TRAIL联合使用可使促凋亡Bcl-2蛋白Bim和Bak从Mcl-1的隔离中释放出来，并促进Bak的构象活化。与对照短发夹RNA（shRNA）细胞相比，Bid的短发夹RNA（shRNA）减弱了半胱天冬酶-8、Bid、半胱天冬酶-3和PARP的裂解，并降低了UMI-77加TRAIL的细胞毒性，表明这种协同作用需要外在和内在凋亡信号之间的相互作用。综上所述，UMI-77通过释放Bim和Bak增强TRAIL诱导的凋亡，这为胶质瘤的治疗提供了一种新的治疗策略。
