High throughput synthetic lethality screen reveals a tumorigenic role of adenylate cyclase in fumarate hydratase-deficient cancer cells.
High throughput synthetic lethality screen reveals a tumorigenic role of adenylate cyclase in fumarate hydratase-deficient cancer cells.
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DOI：
10.1186/1471-2164-15-158
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发表时间：
2014-02-25
期刊：
影响因子：
4.4
通讯作者：
Shlomi T
中科院分区：
文献类型：
--
作者：
Boettcher M;Lawson A;Ladenburger V;Fredebohm J;Wolf J;Hoheisel JD;Frezza C;Shlomi T
合成致死性是一种有吸引力的技术，用于选择性地靶向已经获得与正常细胞不同的分子变化的癌细胞。基于rnai的高通量筛选已成功用于鉴定具有良好特征的肿瘤抑制因子和癌基因的合成致死途径。最近发现的代谢性肿瘤抑制因子表明，合成致死性的概念也可以应用于选择性靶向肿瘤代谢。在这里，我们进行了高通量RNAi筛选，以鉴定富马酸水合酶（FH）的合成致死基因，富马酸水合酶是一种代谢性肿瘤抑制因子，其功能丧失与遗传性平滑肌瘤病和肾细胞癌（HLRCC）有关。根据最近的发现，我们的无偏筛选确定了FH与血红素代谢中的几个基因之间的合成致死性。此外，我们还鉴定了腺苷酸环化酶的合成致死率。在胚胎肾细胞系（HEK293T）和hlrc患者来源的细胞（UOK262）中，通过遗传和药理抑制验证了这种效果。fh缺陷细胞对腺苷酸环化酶的依赖与循环- amp水平的增加是一致的，这可能调节细胞能量代谢。通过腺苷酸环化酶鉴定的FH合成致死性提示了治疗HLRCC患者的一个新的潜在靶点。
Synthetic lethality is an appealing technique for selectively targeting cancer cells which have acquired molecular changes that distinguish them from normal cells. High-throughput RNAi-based screens have been successfully used to identify synthetic lethal pathways with well-characterized tumor suppressors and oncogenes. The recent identification of metabolic tumor suppressors suggests that the concept of synthetic lethality can be applied to selectively target cancer metabolism as well. Here, we perform a high-throughput RNAi screen to identify synthetic lethal genes with fumarate hydratase (FH), a metabolic tumor suppressor whose loss-of-function has been associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Our unbiased screen identified synthetic lethality between FH and several genes in heme metabolism, in accordance with recent findings. Furthermore, we identified an enrichment of synthetic lethality with adenylate cyclases. The effects were validated in an embryonic kidney cell line (HEK293T) and in HLRCC-patient derived cells (UOK262) via both genetic and pharmacological inhibition. The reliance on adenylate cyclases in FH-deficient cells is consistent with increased cyclic-AMP levels, which may act to regulate cellular energy metabolism. The identified synthetic lethality of FH with adenylate cyclases suggests a new potential target for treating HLRCC patients.
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影响因子：
3.7
作者：
Frezza C;Zheng L;Tennant DA;Papkovsky DB;Hedley BA;Kalna G;Watson DG;Gottlieb E
通讯作者：
Gottlieb E
DOI：
10.1152/ajpheart.1997.273.1.h317
发表时间：
1997-07-01
影响因子：
4.8
作者：
Durante, W;Christodoulides, N;Schafer, AI
通讯作者：
Schafer, AI
影响因子：
3.2
作者：
Tseng, CP;Yu, CC;Kuo, JT
通讯作者：
Kuo, JT
全基因组的RNAi筛查鉴定了与RAS癌基因的多种合成致死相互作用。
影响因子：
64.5
作者：
Luo J;Emanuele MJ;Li D;Creighton CJ;Schlabach MR;Westbrook TF;Wong KK;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
--
作者：
Yang Y;Valera VA;Padilla-Nash HM;Sourbier C;Vocke CD;Vira MA;Abu-Asab MS;Bratslavsky G;Tsokos M;Merino MJ;Pinto PA;Srinivasan R;Ried T;Neckers L;Linehan WM
通讯作者：
Linehan WM