GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis.
GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis.
复制标题
DOI：
10.1038/s41467-021-24859-2
复制
发表时间：
2021-08-11
影响因子：
16.6
通讯作者：
Lyssiotis CA
中科院分区：
文献类型：
--
作者：
Kremer DM;Nelson BS;Lin L;Yarosz EL;Halbrook CJ;Kerk SA;Sajjakulnukit P;Myers A;Thurston G;Hou SW;Carpenter ES;Andren AC;Nwosu ZC;Cusmano N;Wisner S;Mbah NE;Shan M;Das NK;Magnuson B;Little AC;Savani MR;Ramos J;Gao T;Sastra SA;Palermo CF;Badgley MA;Zhang L;Asara JM;McBrayer SK;di Magliano MP;Crawford HC;Shah YM;Olive KP;Lyssiotis CA
癌症代谢被重新连接，以支持细胞存活，以应对内在和环境压力。确定针对这些适应的战略是一个积极的研究领域。我们先前描述了胰腺癌中用于维持氧化还原平衡的细胞溶质天冬氨酸氨基转氨酶（GOT1）驱动的通路。在这里，我们试图确定GOT1抑制后的代谢依赖性，以利用胰腺癌的这一特征，并提供对氧化还原代谢调节的额外见解。使用药理学方法，我们确定半胱氨酸，谷胱甘肽和脂质抗氧化功能的代谢脆弱性后GOT1撤出。我们证明，针对任何这些途径触发ferroptosis，氧化，铁依赖性形式的细胞死亡，在GOT1敲低细胞。从机制上讲，我们发现GOT1抑制抑制线粒体代谢，促进分解代谢状态。因此，我们发现这通过自噬增强了不稳定的铁的可用性，从而增强了铁蛋白刺激的活性。总的来说，我们的研究确定了GOT1，铁调节和铁凋亡之间的生化联系。天冬氨酸氨基转氨酶GOT1对维持氧化还原平衡很重要。在这里，作者表明，胰腺癌细胞中GOT1的抑制通过铁凋亡导致细胞死亡。
Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis. The aspartate aminotransaminase GOT1 is important for maintaining redox balance. Here, the authors show that inhibition of GOT1 in pancreatic cancer cells leads to cell death via ferroptosis.
登录
查看更多内容
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
14.8
作者：
Gaschler MM;Andia AA;Liu H;Csuka JM;Hurlocker B;Vaiana CA;Heindel DW;Zuckerman DS;Bos PH;Reznik E;Ye LF;Tyurina YY;Lin AJ;Shchepinov MS;Chan AY;Peguero-Pereira E;Fomich MA;Daniels JD;Bekish AV;Shmanai VV;Kagan VE;Mahal LK;Woerpel KA;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1126/science.aaw9872
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
通讯作者：
Olive KP
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
7.7
作者：
Kühl I;Miranda M;Atanassov I;Kuznetsova I;Hinze Y;Mourier A;Filipovska A;Larsson NG
通讯作者：
Larsson NG