Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity.
Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity.
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精氨酸酶 2 通过生物合成辅因子磷酸吡哆醛消耗和增加多胺毒性抑制肾癌进展
DOI：
10.1016/j.cmet.2018.04.009
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发表时间：
2018-06-05
期刊：
影响因子：
29
通讯作者：
Simon MC
中科院分区：
文献类型：
--
作者：
Ochocki JD;Khare S;Hess M;Ackerman D;Qiu B;Daisak JI;Worth AJ;Lin N;Lee P;Xie H;Li B;Wubbenhorst B;Maguire TG;Nathanson KL;Alwine JC;Blair IA;Nissim I;Keith B;Simon MC
肾癌是世界上十大最常见的恶性肿瘤之一，在过去十年中发病率有所增加。最常见的亚型是“透明细胞”肾细胞癌（ccRCC），其特征在于一致的代谢异常，例如高度升高的糖原和脂质沉积。通过整合代谢组学、基因组学和转录组学数据，我们确定了多种代谢途径中的酶在人类ccRCC肿瘤中普遍耗尽，否则这些肿瘤在遗传上是异质的。值得注意的是，关键尿素循环酶的表达，包括尿素酶2（ARG2）和氨基琥珀酸合酶1（ASS 1），在ccRCC中受到强烈抑制。ARG2活性降低通过至少两种不同的机制促进ccRCC肿瘤生长：保护关键的生物合成辅因子磷酸吡哆醛，并避免有毒的多胺积累。恢复尿素循环酶表达的药理学方法将大大扩展ccRCC患者的治疗策略，目前的治疗仅使一部分肾癌患者受益。Ochocki等人显示，透明细胞肾细胞癌（ccRCC）肿瘤具有改变的氨代谢，其中多种尿素循环酶显著低表达。尿素循环酶抑制酶2（ARG2）的缺失通过保存必需的生物合成辅因子库和防止有毒多胺积聚来促进ccRCC肿瘤进展。
Kidney cancer, one of the ten most prevalent malignancies in the world, has exhibited increased incidence over the last decade. The most common subtype is “clear cell” renal cell carcinoma (ccRCC), which features consistent metabolic abnormalities, such as highly elevated glycogen and lipid deposition. By integrating metabolomic, genomic, and transcriptomic data, we determined that enzymes in multiple metabolic pathways are universally depleted in human ccRCC tumors, which are otherwise genetically heterogeneous. Notably, the expression of key urea cycle enzymes, including arginase 2 (ARG2) and argininosuccinate synthase 1 (ASS1), is strongly repressed in ccRCC. Reduced ARG2 activity promotes ccRCC tumor growth through at least two distinct mechanisms: conserving the critical biosynthetic cofactor pyridoxal phosphate, and avoiding toxic polyamine accumulation. Pharmacological approaches to restore urea cycle enzyme expression would greatly expand treatment strategies for ccRCC patients, where current therapies only benefit a subset of those afflicted with renal cancer. Ochocki et al. show that clear cell renal cell carcinoma (ccRCC) tumors have altered ammoniametabolism with multiple urea cycle enzymes being significantly underexpressed. Loss of the urea cycle enzyme arginase2 (ARG2) promotes ccRCC tumor progression by conserving essential biosynthetic cofactor pools and preventing toxic polyamine build up.
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影响因子：
3.7
作者：
Ivanov DP;Parker TL;Walker DA;Alexander C;Ashford MB;Gellert PR;Garnett MC
通讯作者：
Garnett MC
各种各样的癌症相关MTOR突变是过度激活的，可以预测雷帕霉素的敏感性。
影响因子：
28.2
作者：
Grabiner BC;Nardi V;Birsoy K;Possemato R;Shen K;Sinha S;Jordan A;Beck AH;Sabatini DM
通讯作者：
Sabatini DM
小鼠肾细胞癌建模：Bap1 和 Pbrm1 失活驱动肿瘤分级。
影响因子：
28.2
作者：
Gu YF;Cohn S;Christie A;McKenzie T;Wolff N;Do QN;Madhuranthakam AJ;Pedrosa I;Wang T;Dey A;Busslinger M;Xie XJ;Hammer RE;McKay RM;Kapur P;Brugarolas J
通讯作者：
Brugarolas J
DOI：
10.1016/j.urolonc.2017.01.017
发表时间：
2017-04
期刊：
Urologic oncology
影响因子：
--
作者：
Joseph RW;Chatta G;Vaishampayan U
通讯作者：
Vaishampayan U
DOI：
10.1073/pnas.1307237110
发表时间：
2013-05-28
影响因子：
11.1
作者：
Kamphorst, Jurre J.;Cross, Justin R.;Rabinowitz, Joshua D.
通讯作者：
Rabinowitz, Joshua D.