Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries.
Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries.
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卵巢透明细胞癌中靶向线粒体代谢。
DOI：
10.3390/ijms22094750
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发表时间：
2021-04-29
影响因子：
5.6
通讯作者：
Bazzaro M
中科院分区：
文献类型：
--
作者：
Zhang X;Shetty M;Clemente V;Linder S;Bazzaro M
卵巢透明细胞癌是一种罕见的化疗难治性肿瘤。大约50%的OCCC患者有ARID 1A失活突变，ARID 1A是SWI/SNF染色质重塑复合物的成员。SWI/SNF重塑的成员已经成为哺乳动物细胞能量代谢的调节剂;然而，ARID 1A作为OCCC中线粒体代谢的调节剂的作用尚未确定。在这里，我们表明，ARID 1A损失的结果增加线粒体代谢，并使ARID 1A突变的细胞越来越多地和选择性地依赖于it. The增加线粒体活性ARID 1A损失后，与c-Myc表达增加和线粒体数量增加和减少其大小与较高的线粒体嵴/外膜比一致。值得注意的是，复合物I线粒体抑制剂IACS-010759的临床前测试显示，它延长了ARID 1A突变OCCC临床前模型的总生存期。这些发现提供了ARID 1A突变的OCCC中的靶向线粒体活性。
Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A, a member of the SWI/SNF chromatin-remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells; however, the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here, we show that ARID1A loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated with increase in c-Myc expression and increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 showed it extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide for the targeting mitochondrial activity in ARID1A-mutated OCCCs.
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影响因子：
16.6
作者：
Anderson GR;Wardell SE;Cakir M;Yip C;Ahn YR;Ali M;Yllanes AP;Chao CA;McDonnell DP;Wood KC
通讯作者：
Wood KC
影响因子：
64.8
作者：
Lee JE;Westrate LM;Wu H;Page C;Voeltz GK
通讯作者：
Voeltz GK
DOI：
10.1084/jem.20172168
发表时间：
2018-09-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cichocki F;Wu CY;Zhang B;Felices M;Tesi B;Tuininga K;Dougherty P;Taras E;Hinderlie P;Blazar BR;Bryceson YT;Miller JS
通讯作者：
Miller JS
影响因子：
--
作者：
Kwan SY;Cheng X;Tsang YT;Choi JS;Kwan SY;Izaguirre DI;Kwan HS;Gershenson DM;Wong KK
通讯作者：
Wong KK
影响因子：
82.9
作者：
Lissanu Deribe Y;Sun Y;Terranova C;Khan F;Martinez-Ledesma J;Gay J;Gao G;Mullinax RA;Khor T;Feng N;Lin YH;Wu CC;Reyes C;Peng Q;Robinson F;Inoue A;Kochat V;Liu CG;Asara JM;Moran C;Muller F;Wang J;Fang B;Papadimitrakopoulou V;Wistuba II;Rai K;Marszalek J;Futreal PA
通讯作者：
Futreal PA