Modulation of energy metabolism to overcome drug resistance in chronic myeloid leukemia cells through induction of autophagy

Author:

Li Yiqing,Zeng Peiting,Xiao Jie,Huang Peng,Liu PanpanORCID

Abstract

AbstractTyrosine kinase inhibitors (TKIs) such as imatinib (IM) are key drugs for treatment of chronic myeloid leukemia (CML). Development of drug resistance to TKIs due to BCR-ABL mutation, especially T315I mutation, poses a major challenge in the clinical treatment of CML. The purpose of this study was to test metabolic modulation as a potential strategy to overcome imatinib resistance based on the possible crosstalk between BCR-ABL signaling and metabolic changes in CML. 2-deoxy-d-glucose (2-DG) was used to modulate the glucose metabolism in CML cells sensitive to IM (KBM5 cell line) and resistant to imatinib with BCR-ABL T315I mutation (KBM5-T315I cell line). Seahorse XFe24 extracellular flux analyzer to quantify oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) was used to measure cellular energy metabolism. Cell proliferation was analyzed by CCK-8 assay and MTS assay. Annexin V/PI staining was used to evaluate cell apoptosis. Autophagy-related proteins and enzyme/proteins were detected by Western blotting. Cellular ATP concentration was detected using an ATP-based Cell Titer Kit. The combined action of 2-DG and IM was evaluated by calculating the drug combination index. Our results found that inhibition of glucose metabolism by 2-DG significantly impaired the viability of CML cells and co-treatment with 2-DG and imatinib induced a synergistic inhibition of KBM5 and KBM5-T315I cells. 2-DG induced cell death by autophagy, not by apoptosis, as evidenced by increased expression of Beclin1 and LC3AII and lack of annexin V/PI-positive cells. At the biochemical level, 2-DG inhibited glycolysis and mitochondrial oxygen consumption manifested by a significant decrease in ECAR and OCR, and a depletion of ATP. The severe metabolic stress induced by 2-DG in CML cells led to autophagic cell death. Our results suggested a metabolic vulnerability of CML cells that could be targeted by a combination of 2-DG and imatinib as an alternative treatment for imatinib-resistant CML.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Guangdong Province

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3