Zhang Yu, Li Xin, Tan Shisheng, Liu Xinyu, Zhao Xinyu, Yuan Zhu, Nie Chunlai
Departmant of Oncology, Guizhou People's Hospital, Guizhou, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China.
Oncotarget. 2017 Feb 14;8(7):11042-11052. doi: 10.18632/oncotarget.14223.
The regulation of Mcl-1 expression is necessary for the induction of cancer cell apoptosis by ABTs such as ABT-737, ABT-263 and ABT-199. However, the reduction in Mcl-1 expression is not sufficient for initiating cell death in hematopoietic cancer cells with high Bcl-xL expression. Here, we demonstrate that 2-deoxyglucose (2-DG) enhanced the effect of ABT-199 to induce cell apoptosis in hematologic malignancies with up-regulated Bcl-xL expression. Our study revealed that 2-DG could decrease glucose-dependent and Akt-independent Mcl-1 expression, which is mediated by the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Moreover, the combination of 2-DG and ABT-199 triggered c-Jun NH2-terminal kinase (JNK) phosphorylation and subsequent Bcl-xL degradation, whereas 2-DG and ABT-199 alone had little effect on JNK activation. Therefore, the combination of 2-DG and ABT-199 initiated cell death through the reduction of Mcl-1 expression and JNK activation. Our study could provide a clinical theoretical basis for the use of ABT-199 in hematologic malignancies with excessive Bcl-xL expression.
Mcl-1表达的调控对于ABT-737、ABT-263和ABT-199等ABT类药物诱导癌细胞凋亡是必要的。然而，在Bcl-xL表达较高的造血癌细胞中，Mcl-1表达的降低不足以引发细胞死亡。在此，我们证明2-脱氧葡萄糖（2-DG）增强了ABT-199在Bcl-xL表达上调的血液系统恶性肿瘤中诱导细胞凋亡的作用。我们的研究表明，2-DG可降低由雷帕霉素复合物1（mTORC1）途径介导的葡萄糖依赖性和Akt非依赖性Mcl-1表达。此外，2-DG与ABT-199联合可触发c-Jun氨基末端激酶（JNK）磷酸化及随后的Bcl-xL降解，而单独的2-DG和ABT-199对JNK激活几乎没有影响。因此，2-DG与ABT-199联合通过降低Mcl-1表达和激活JNK引发细胞死亡。我们的研究可为ABT-199在Bcl-xL表达过高的血液系统恶性肿瘤中的应用提供临床理论依据。
