Dichloroacetic acid and rapamycin synergistically inhibit tumor progression
Dichloroacetic acid and rapamycin synergistically inhibit tumor progression
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二氯乙酸和雷帕霉素协同抑制肿瘤进展
DOI：
10.1631/jzus.b2200356
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发表时间：
2023
影响因子：
5.1
通讯作者：
Hai
中科院分区：
文献类型：
--
作者：
Huan Chen;Kunming Liang;Cong Hou;Hai
哺乳动物雷帕霉素靶蛋白（mTOR）控制细胞凋亡，并且mTOR信号在大多数癌细胞中过度活跃。因此，抑制mTOR信号传导有益于癌症患者。雷帕霉素是美国食品和药物管理局（FDA）批准的药物，是一种特异性mTOR复合物1（mTORC 1）抑制剂，用于治疗几种不同类型的癌症。然而，据报道雷帕霉素抑制癌症生长而不是诱导细胞凋亡。丙酮酸脱氢酶复合物（PDHc）是线粒体丙酮酸氧化的看门人。已经在许多癌细胞中观察到PDHc失活，并且这种改变保护癌细胞免于衰老和烟酰胺腺嘌呤二核苷酸（NAD+）耗尽。在本文中，我们描述了我们的发现，雷帕霉素治疗促进丙酮酸脱氢酶E1亚基α 1（PDHA1）磷酸化，并导致PDHc失活依赖于细胞中的mTOR信号转导抑制。这种失活降低了癌细胞对雷帕霉素反应的敏感性。因此，用丙酮酸脱氢酶激酶（PDK）抑制剂二氯乙酸（DCA）重新启动PDHc活性，在体外和体内促进癌细胞对雷帕霉素治疗的易感性。
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.
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影响因子：
50.3
作者：
Valvezan AJ;Turner M;Belaid A;Lam HC;Miller SK;McNamara MC;Baglini C;Housden BE;Perrimon N;Kwiatkowski DJ;Asara JM;Henske EP;Manning BD
通讯作者：
Manning BD
影响因子：
28.2
作者：
Rodrik-Outmezguine VS;Chandarlapaty S;Pagano NC;Poulikakos PI;Scaltriti M;Moskatel E;Baselga J;Guichard S;Rosen N
通讯作者：
Rosen N
影响因子：
16
作者：
Sarbassov, DD;Ali, SM;Sabatini, DM
通讯作者：
Sabatini, DM
影响因子：
50.3
作者：
Fan Q;Aksoy O;Wong RA;Ilkhanizadeh S;Novotny CJ;Gustafson WC;Truong AY;Cayanan G;Simonds EF;Haas-Kogan D;Phillips JJ;Nicolaides T;Okaniwa M;Shokat KM;Weiss WA
通讯作者：
Weiss WA
影响因子：
50.3
作者：
Phung, Thuy L.;Ziv, Keren;Benjamin, Laura E.
通讯作者：
Benjamin, Laura E.