Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.
Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.
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DOI：
10.1053/j.gastro.2021.06.045
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发表时间：
2021-11
期刊：
影响因子：
29.4
通讯作者：
Singh PK
中科院分区：
文献类型：
--
作者：
Hu T;Shukla SK;Vernucci E;He C;Wang D;King RJ;Jha K;Siddhanta K;Mullen NJ;Attri KS;Murthy D;Chaika NV;Thakur R;Mulder SE;Pacheco CG;Fu X;High RR;Yu F;Lazenby A;Steegborn C;Lan P;Mehla K;Rotili D;Chaudhary S;Valente S;Tafani M;Mai A;Auwerx J;Verdin E;Tuveson D;Singh PK
SIRT 5通过翻译后修饰发挥多效性作用，在不同的肿瘤中充当肿瘤抑制基因或癌基因。然而，SIRT 5在胰腺导管腺癌（PDAC）的发生和发展中所起的作用仍然未知。使用具有SIRT 5染色的已发表数据集和组织阵列来研究SIRT 5在PDAC中的临床相关性。此外，为了确定SIRT 5在PDAC致癌中的作用，我们产生了具有条件性Sirt 5敲除的本地小鼠模型。此外，为了研究SIRT 5在PDAC致癌作用中的机制作用，在PDAC细胞系和类器官中敲低SIRT 5，然后进行代谢组学和蛋白质组学研究。新型SIRT 5激活剂用于类器官和患者来源的异种移植物的治疗研究。SIRT 5表达负调节肿瘤细胞增殖，并与PDAC患者的良好预后相关。PDAC小鼠模型中Sirt 5的基因切除促进了腺泡-导管化生、前驱病变和胰腺肿瘤发生，导致存活率低。从机制上讲，SIRT 5的损失通过乙酰化介导的GOT 1激活增强谷氨酰胺和谷胱甘肽代谢。选择性SIRT 5激活剂MC 3138表型模仿SIRT 5过表达的作用，并对人PDAC细胞表现出抗肿瘤作用。MC 3138还减少了核苷酸库，使人PDAC细胞系、类器官和患者来源的异种移植物对吉西他滨敏感。总的来说，我们确定SIRT 5是PDAC中的关键肿瘤抑制因子，其缺失通过增加GOT 1对谷氨酰胺的非经典利用促进肿瘤发生，并且SIRT 5激活是靶向PDAC的新型治疗策略。
SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was utilized for therapeutic studies in organoids and patient-derived xenografts. SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in PDAC patients. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited anti-tumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased non-canonical utilization of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.
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影响因子：
16
作者：
Nishida Y;Rardin MJ;Carrico C;He W;Sahu AK;Gut P;Najjar R;Fitch M;Hellerstein M;Gibson BW;Verdin E
通讯作者：
Verdin E
Sirtuin5 通过以去谷氨酰化依赖性方式增强谷氨酰胺分解而促进结直肠癌发生。
影响因子：
16.6
作者：
Wang YQ;Wang HL;Xu J;Tan J;Fu LN;Wang JL;Zou TH;Sun DF;Gao QY;Chen YX;Fang JY
通讯作者：
Fang JY
影响因子：
29.4
作者：
Strobel, Oliver;Dor, Yuval;Thayer, Sarah P.
通讯作者：
Thayer, Sarah P.
DOI：
10.1073/pnas.1911954116
发表时间：
2019-12-26
影响因子：
11.1
作者：
Greene, Kai Su;Lukey, Michael J.;Cerione, Richard A.
通讯作者：
Cerione, Richard A.
SIRT5 调节线粒体赖氨酸琥珀酰组和代谢网络。
影响因子：
29
作者：
Rardin MJ;He W;Nishida Y;Newman JC;Carrico C;Danielson SR;Guo A;Gut P;Sahu AK;Li B;Uppala R;Fitch M;Riiff T;Zhu L;Zhou J;Mulhern D;Stevens RD;Ilkayeva OR;Newgard CB;Jacobson MP;Hellerstein M;Goetzman ES;Gibson BW;Verdin E
通讯作者：
Verdin E