Dichloroacetic acid and rapamycin synergistically inhibit tumor progression

作     者：Huan CHEN Kunming LIANG Cong HOU Hai-long PIAO Huan CHEN;Kunming LIANG;Cong HOU;Hai-long PIAO

作者机构：CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalian 116023China Department of Biochemistry&Molecular BiologySchool of Life SciencesChina Medical UniversityShenyang 110122China University of Chinese Academy of SciencesBeijing 100049China 

出 版 物：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 (浙江大学学报（英文版）B辑（生物医学与生物技术）)

年 卷 期：2023年第24卷第5期

页      面：397-405页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 0836[工学-生物工程] 10[医学] 

基　　金：supported by the National Key Research and Development Program of China(No.2022YFA0806503) the National Natural Science Foundation of China(No.81972625) the Dalian Science and Technology Innovation Funding(No.2019J12SN52) the Liaoning Revitalization Talents Program(No.XLYC2002035),China。 

主　　题：Dichloroacetic acid(DCA) Rapamycin Pyruvate dehydrogenase E1 subunit alpha 1(PDHA1) Mammalian target of rapamycin(mTOR) 

摘      要：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.