Cell-surface G-protein-coupled receptors for tumor-associated metabolites: A direct link to mitochondrial dysfunction in cancer.
Cell-surface G-protein-coupled receptors for tumor-associated metabolites: A direct link to mitochondrial dysfunction in cancer.
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DOI：
10.1016/j.bbcan.2017.05.003
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Ganapathy V
中科院分区：
文献类型：
--
作者：
Ristic B;Bhutia YD;Ganapathy V
线粒体是丙酮酸氧化、柠檬酸循环、氧化磷酸化、酮合成和脂肪酸氧化的场所。线粒体功能的减弱是肿瘤细胞中发生的最重要的变化之一，与肿瘤发生、血管生成、Warburg效应和表观遗传学直接相关。特别是，在癌症中有三种线粒体酶失活：丙酮酸脱氢酶(PDH)、琥珀酸脱氢酶(SDH)和3-羟基-3-甲基戊二酰辅酶A合成酶-2(HMGCS2)。这些酶通过乙酰化/去乙酰化受到调节。SIRT3是主要的线粒体脱乙酰酶，直接针对这些酶进行脱乙酰化，并保持它们的最佳催化活性。SIRT3是一种肿瘤抑制因子，这些酶的脱乙酰基参与了它的生物学功能。丙酮酸氧化脱羧制乙酰辅酶A，琥珀酸氧化成富马酸，HMGCS2控制酮体β-羟基丁酸酯的合成。由于癌症中这些酶的活性降低，肿瘤细胞积累乳酸和琥珀酸，但产生较少的β-羟丁酸。除了它们在细胞能量学中的作用外，这些代谢物还通过特定的细胞表面G蛋白偶联受体作为信号分子发挥作用。乳酸信号通过Gpr81，琥珀酸信号通过Gpr91，β-羟丁酸信号通过Gpr109a。此外，乳酸可激活缺氧诱导因子HIF1DNA，琥珀酸可促进α甲基化。GPR81和GPR91是肿瘤促进剂，它们的激动剂通过这两个受体增强信号，从而增加乳酸和琥珀酸的产生，从而推动肿瘤的发生。相反，GPr109a是一种肿瘤抑制因子，其激动剂β-羟丁酸的合成减少，从而抑制了通过该受体的信号转导，从而减弱了Gpr109a的抑瘤作用。与乳酸/琥珀酸和β-羟丁酸水平相反的变化同时，肿瘤细胞上调GPR81和GPR91，但下调GPR109a。因此，这三种代谢物受体在癌症中起着关键作用，代表着一类新的药物靶点，包括用于癌症治疗的选择性GPR81和GPR91拮抗剂以及用于预防癌症的GPR109a激动剂。
Mitochondria are the sites of pyruvate oxidation, citric acid cycle, oxidative phosphorylation, ketogenesis, and fatty acid oxidation. Attenuation of mitochondrial function is one of the most significant changes that occurs in tumor cells, directly linked to oncogenesis, angiogenesis, Warburg effect, and epigenetics. In particular, three mitochondrial enzymes are inactivated in cancer: pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and 3-hydroxy-3-methylglutaryl CoA synthase-2 (HMGCS2). These enzymes are subject to regulation via acetylation/deacetylation. SIRT3, the predominant mitochondrial deacetylase, directly targets these enzymes for deacetylation and maintains their optimal catalytic activity. SIRT3 is a tumor suppressor, and deacetylation of these enzymes contributes to its biological function. PDH catalyzes the oxidative decarboxylation of pyruvate into acetyl CoA, SDH oxidizes succinate into fumarate, and HMGCS2 controls the synthesis of the ketone body β-hydroxybutyrate. As the activities of these enzymes are decreased in cancer, tumor cells accumulate lactate and succinate but produce less amounts of β-hydroxybutyrate. Apart from their role in cellular energetics, these metabolites function as signaling molecules via specific cell-surface G-protein-coupled receptors. Lactate signals via GPR81, succinate via GPR91, and β-hydroxybutyrate via GPR109A. In addition, lactate activates hypoxia-inducible factor HIF1α and succinate promotes DNA methylation. GPR81 and GPR91 are tumor promoters, and increased production of lactate and succinate as their agonists drives tumorigenesis by enhancing signaling via these two receptors. In contrast, GPR109A is a tumor suppressor, and decreased synthesis of β-hydroxybutyrate as its agonist suppresses signaling via this receptor, thus attenuating the tumor-suppressing function of GPR109A. In parallel with the opposing changes in lactate/succinate and β-hydroxybutyrate levels, tumor cells upregulate GPR81 and GPR91 but downregulate GPR109A. As such, these three metabolite receptors play a critical role in cancer and represent a new class of drug targets with selective antagonists of GPR81 and GPR91 for cancer treatment and agonists of GPR109A for cancer prevention.
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影响因子：
16
作者：
Fan, Jun;Shan, Changliang;Kang, Hee-Bum;Elf, Shannon;Xie, Jianxin;Tucker, Meghan;Gu, Ting-Lei;Aguiar, Mike;Lonning, Scott;Chen, Huaibin;Mohammadi, Moosa;Britton, Laura-Mae P.;Garcia, Benjamin A.;Aleckovic, Masa;Kang, Yibin;Kaluz, Stefan;Devi, Nara;Van Meir, Erwin G.;Hitosugi, Taro;Seo, Jae Ho;Lonial, Sagar;Gaddh, Manila;Arellano, Martha;Khoury, Hanna J.;Khuri, Fadlo R.;Boggon, Titus J.;Kang, Sumin;Chen, Jing
通讯作者：
Chen, Jing
影响因子：
--
作者：
Bhutia YD;Ogura J;Sivaprakasam S;Ganapathy V
通讯作者：
Ganapathy V
DOI：
10.1042/bcj20160068
发表时间：
2016-06-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Bhutia YD;Babu E;Ganapathy V
通讯作者：
Ganapathy V
影响因子：
3.7
作者：
Brown NJ;Higham SE;Perunovic B;Arafa M;Balasubramanian S;Rehman I
通讯作者：
Rehman I
DOI：
10.1016/j.bbabio.2010.10.023
发表时间：
2011-06
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Chandra D;Singh KK
通讯作者：
Singh KK