Oncotarget

Research Papers:

Mcl-1 expression and JNK activation induces a threshold for apoptosis in Bcl-xL-overexpressing hematopoietic cells

Yu Zhang, Xin Li, Shisheng Tan, Xinyu Liu, Xinyu Zhao, Zhu Yuan and Chunlai Nie _

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Oncotarget. 2017; 8:11042-11052. https://doi.org/10.18632/oncotarget.14223

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Abstract

Yu Zhang1,*, Xin Li1,*, Shisheng Tan1, Xinyu Liu2, Xinyu Zhao2, Zhu Yuan2, Chunlai Nie2

1Departmant of Oncology, Guizhou People’s Hospital, Guizhou, China

2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China

*These authors contributed equally to this work

Correspondence to:

Chunlai Nie, email: [email protected]

Shisheng Tan, email: [email protected]

Keywords: 2-DG, ABT-199, Apoptosis, Bcl-xL, Mcl-1

Received: November 02, 2016     Accepted: December 20, 2016     Published: December 26, 2016

ABSTRACT

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.


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