Pharmacological and genetic perturbation establish SIRT5 as a promising target in breast cancer.
Pharmacological and genetic perturbation establish SIRT5 as a promising target in breast cancer.
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药理学和遗传学扰动使SIRT5成为乳腺癌中有希望的靶点。
DOI：
10.1038/s41388-020-01637-w
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发表时间：
2021-03
期刊：
影响因子：
8
通讯作者：
Weiss RS
中科院分区：
文献类型：
--
作者：
Abril YLN;Fernandez IR;Hong JY;Chiang YL;Kutateladze DA;Zhao Q;Yang M;Hu J;Sadhukhan S;Li B;He B;Remick B;Bai JJ;Mullmann J;Wang F;Maymi V;Dhawan R;Auwerx J;Southard T;Cerione RA;Lin H;Weiss RS
SIRT5是sirtuin家族的一员，该家族是NAD+依赖性蛋白赖氨酸脱酰酶，参与多种生理过程。SIRT5从赖氨酸残基中去除带负电荷的丙二酰、琥珀酰和戊二酰基团，从而调节参与细胞代谢和其他生物过程的多种酶。SIRT5在人类乳腺癌和其他恶性肿瘤中过度表达，但对SIRT5抑制治疗癌症的治疗潜力知之甚少。在这里，我们报道了SIRT5在乳腺癌细胞系和小鼠模型中的遗传破坏，导致IDH2和其他代谢酶的琥珀酰化增加，氧化应激增加，转化和肿瘤发生受损。因此，我们开发了有效的、选择性的、细胞渗透性的小分子SIRT5抑制剂。在基因工程和异种移植小鼠模型中，SIRT5抑制抑制了培养的乳腺癌细胞的转化特性，并显著降低了乳腺肿瘤的生长。考虑到Sirt5敲除小鼠通常是正常的，只观察到轻微的表型，这些数据表明Sirt5是治疗乳腺癌的一个有希望的靶点。新的SIRT5抑制剂为未来SIRT5的研究提供了有用的探针，并为靶向SIRT5作为治疗策略提供了途径。
SIRT5 is a member of the sirtuin family of NAD+-dependent protein lysine deacylases implicated in a variety of physiological processes. SIRT5 removes negatively charged malonyl, succinyl, and glutaryl groups from lysine residues and thereby regulates multiple enzymes involved in cellular metabolism and other biological processes. SIRT5 is overexpressed in human breast cancers and other malignancies, but little is known about the therapeutic potential of SIRT5 inhibition for treating cancer. Here we report that genetic SIRT5 disruption in breast cancer cell lines and mouse models caused increased succinylation of IDH2 and other metabolic enzymes, increased oxidative stress, and impaired transformation and tumorigenesis. We therefore developed potent, selective, and cell permeable small molecule SIRT5 inhibitors. SIRT5 inhibition suppressed the transformed properties of cultured breast cancer cells and significantly reduced mammary tumor growth in vivo, in both genetically engineered and xenotransplant mouse models. Considering that Sirt5 knockout mice are generally normal, with only mild phenotypes observed, these data establish SIRT5 as a promising target for treating breast cancer. The new SIRT5 inhibitors provide useful probes for future investigations of SIRT5 and an avenue for targeting SIRT5 as a therapeutic strategy.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
Jiang L;Shestov AA;Swain P;Yang C;Parker SJ;Wang QA;Terada LS;Adams ND;McCabe MT;Pietrak B;Schmidt S;Metallo CM;Dranka BP;Schwartz B;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
3.4
作者：
Chang, Liang;Xi, Liang;Jian, Zhixiang
通讯作者：
Jian, Zhixiang
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.