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On-line Access: 2023-05-15

Received: 2022-07-03

Revision Accepted: 2022-12-07

Crosschecked: 2023-05-16

Cited: 0

Clicked: 736

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Hailong PIAO

https://orcid.org/0000-0001-7451-0386

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Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.5 P.397-405

http://doi.org/10.1631/jzus.B2200356


Dichloroacetic acid and rapamycin synergistically inhibit tumor progression


Author(s):  Huan CHEN, Kunming LIANG, Cong HOU, Hai-long PIAO

Affiliation(s):  CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; more

Corresponding email(s):   hpiao@dicp.ac.cn

Key Words:  Dichloroacetic acid (DCA), Rapamycin, Pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), Mammalian target of rapamycin (mTOR)


Huan CHEN, Kunming LIANG, Cong HOU, Hai-long PIAO. Dichloroacetic acid and rapamycin synergistically inhibit tumor progression[J]. Journal of Zhejiang University Science B, 2023, 24(5): 397-405.

@article{title="Dichloroacetic acid and rapamycin synergistically inhibit tumor progression",
author="Huan CHEN, Kunming LIANG, Cong HOU, Hai-long PIAO",
journal="Journal of Zhejiang University Science B",
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pages="397-405",
year="2023",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200356"
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%T Dichloroacetic acid and rapamycin synergistically inhibit tumor progression
%A Huan CHEN
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%A Hai-long PIAO
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T1 - Dichloroacetic acid and rapamycin synergistically inhibit tumor progression
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PB - Zhejiang University Press & Springer
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DOI - 10.1631/jzus.B2200356


Abstract: 
Mammalian target of rapamycin (mTOR) controls cellular anabolism, and mTOR signaling is hyperactive in most cancer cells. As a result, inhibition of mTOR signaling benefits cancer patients. rapamycin is a US Food and Drug Administration (FDA)-approved drug, a specific mTOR complex 1 (mTORC1) inhibitor, for the treatment of several different types of cancer. However, rapamycin is reported to inhibit cancer growth rather than induce apoptosis. Pyruvate dehydrogenase complex (PDHc) is the gatekeeper for mitochondrial pyruvate oxidation. PDHc inactivation has been observed in a number of cancer cells, and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide (NAD+‍) exhaustion. In this paper, we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells. This inactivation reduces the sensitivity of cancer cells’ response to rapamycin. As a result, rebooting PDHc activity with dichloroacetic acid (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, promotes cancer cells’ susceptibility to rapamycin treatment in vitro and in vivo.

二氯乙酸联合雷帕霉素协同抑制肿瘤进程

陈欢1,3, 梁昆明2, 侯聪1, 朴海龙1,2,3
1中国科学院分析化学分离科学重点实验室,中国科学院大连化学物理研究所,中国大连市,116023
2中国医科大学生命学院,生命化学与分子生物学系,中国沈阳市,110122
3中国科学院大学,中国北京市,100049
摘要:哺乳动物雷帕霉素靶蛋白(mTOR)控制细胞的合成代谢,并且在大多数的肿瘤细胞中mTOR信号通路高度活化,因此抑制mTOR信号通路对癌症患者有益。雷帕霉素是一种美国食品药品监督管理局(FDA)批准的临床一线药物,是mTORC1的特异性抑制剂,用于治疗多种不同类型的癌症。然而,研究发现雷帕霉素仅抑制肿瘤细胞的增殖并不引起细胞的凋亡。丙酮酸脱氢酶复合体(PDHc)在线粒体丙酮酸氧化过程起着决定作用。许多肿瘤细胞中的PDHc处于失活状态,这一变化可以使肿瘤细胞免于衰老和NAD+耗竭。本研究中,雷帕霉素处理细胞导致依赖mTOR信号通路抑制的丙酸脱氢酶α1(PDHA1)磷酸化水平升高,并导致PDHc酶活降低。PDHc失活直接引起肿瘤细胞对雷帕霉素敏感度下降。因此,在体内和体外的实验中通过使用丙酮酸脱氢酶激酶(PDK)的抑制剂二氯乙酸(DCA)可以重新激活PDHc的活力,进而增加肿瘤细胞对雷帕霉素的敏感性。

关键词:二氯乙酸(DCA);雷帕霉素;丙酸脱氢酶α1(PDHA1);哺乳动物雷帕霉素靶蛋白(mTOR)

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