Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers.
Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers.
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DOI：
10.1016/j.celrep.2016.12.077
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发表时间：
2017-01-24
期刊：
影响因子：
8.8
通讯作者：
Van Tine BA
中科院分区：
文献类型：
--
作者：
Kremer JC;Prudner BC;Lange SES;Bean GR;Schultze MB;Brashears CB;Radyk MD;Redlich N;Tzeng SC;Kami K;Shelton L;Li A;Morgan Z;Bomalaski JS;Tsukamoto T;McConathy J;Michel LS;Held JM;Van Tine BA
靶向代谢缺陷是治疗癌症的未充分利用的策略。精氨酸营养缺陷型是由腺苷琥珀酸合成酶1（ASS1）的沉默引起的，是广泛的侵袭性癌症中报道的常见代谢改变。为了评估ASS 1缺陷细胞系中急性和慢性精氨酸饥饿引起的代谢效应，我们进行了代谢物分析。我们发现，精氨酸诱导的耗竭导致丝氨酸生物合成增加，谷氨酰胺回补，氧化磷酸化，有氧糖酵解减少，有效地抑制了瓦尔堡效应。细胞中糖酵解的减少，否则依赖于有氧糖酵解，与PKM2表达和磷酸化的减少以及PHGDH的上调相关。同时精氨酸剥夺和转氨酶抑制被发现是合成致死的范围内的ASS 1缺陷型肿瘤细胞系，并足以导致在小鼠体内肿瘤消退。这些结果确定了两种利用ASS 1阴性癌症的代谢脆弱性的合成致死治疗策略。Kremer等人使用全局代谢组学分析和稳定同位素示踪表明，ASS 1缺陷型肿瘤的精氨酸饥饿导致丝氨酸生物合成、谷氨酰胺回补和氧化磷酸化增加，同时有氧糖酵解减少。精氨酸剥夺的逃逸途径的药理学抑制表现出合成的致死相互作用。
Targeting defects in metabolism is an underutilized strategy for the treatment of cancer. Arginine auxotrophy resulting from the silencing of argininosuccinate synthetase 1 (ASS1) is a common metabolic alteration reported in a broad range of aggressive cancers. To assess the metabolic effects that arise from acute and chronic arginine starvation in ASS1-deficient cell lines, we performed metabolite profiling. We found that pharmacologically induced arginine depletion causes increased serine biosynthesis, glutamine anaplerosis, oxidative phosphorylation, and decreased aerobic glycolysis, effectively inhibiting the Warburg effect. The reduction of glycolysis in cells otherwise dependent on aerobic glycolysis is correlated with reduced PKM2 expression and phosphorylation and upregulation of PHGDH. Concurrent arginine deprivation and glutaminase inhibition was found to be synthetic lethal across a spectrum of ASS1-deficient tumor cell lines and is sufficient to cause in vivo tumor regression in mice. These results identify two synthetic lethal therapeutic strategies exploiting metabolic vulnerabilities of ASS1-negative cancers. Using global metabolomics analysis and stable isotope tracing, Kremer et al. show that arginine starvation of ASS1-deficient tumors causes an increase in serine biosynthesis, glutamine anaplerosis, and oxidative phosphorylation with a simultaneous decrease in aerobic glycolysis. Pharmacological inhibition of escape pathways to arginine deprivation exhibits a synthetic lethal interaction.
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影响因子：
11.2
作者：
Kim, Randie H.;Coates, Jodi M.;Bowles, Tawnya L.;McNerney, Gregory P.;Sutcliffe, Julie;Jung, Jae U.;Gandour-Edwards, Regina;Chuang, Frank Y. S.;Bold, Richard J.;Kung, Hsing Jien
通讯作者：
Kung, Hsing Jien
DOI：
10.1073/pnas.1404171111
发表时间：
2014-09-30
影响因子：
11.1
作者：
Changou, Chun A.;Chen, Yun-Ru;Kung, Hsing-Jien
通讯作者：
Kung, Hsing-Jien
影响因子：
45.3
作者：
Izzo, F;Marra, P;Curley, SA
通讯作者：
Curley, SA
影响因子：
6.2
作者：
Dillon, BJ;Prieto, VG;Clark, MA
通讯作者：
Clark, MA
影响因子：
28.2
作者：
Cantor JR;Sabatini DM
通讯作者：
Sabatini DM