Targeting Dependency on the GPX4 Lipid Peroxide Repair Pathway for Cancer Therapy.
Targeting Dependency on the GPX4 Lipid Peroxide Repair Pathway for Cancer Therapy.
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DOI：
10.1021/acs.biochem.8b00307
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发表时间：
2018-04-10
期刊：
影响因子：
2.9
通讯作者：
Stockwell BR
中科院分区：
文献类型：
--
作者：
Liu H;Schreiber SL;Stockwell BR
细胞依赖于它们的脂质组成来建立和调节膜结构完整性、形态、代谢和其他细胞功能。例如，在组成真核细胞膜的数千种脂质中，含多不饱和脂肪酸（PUFA）的磷脂（PUFA- pls）的丰度和定位是决定细胞膜流动性的主要因素。由于pufa中双键的顺式构象阻碍了这些脂肪酸尾部的有效堆积，PUFA-PLs水平的升高有助于增加膜的流动性和变薄。然而，PUFAs容易通过与双烯丙基位置的分子氧反应，由脂氧合酶催化或通过非酶机制进行脂质过氧化。例如，氧化PUFAs可以作为脂质信号，调节炎症过程。然而，过氧pufas容易分解成活性物质，从而破坏生物分子，如蛋白质和核酸。因此，细胞依赖于一个关键的蛋白质网络来修复PUFA-PL过氧化物。这个修复网络中心的一个关键蛋白是硒蛋白谷胱甘肽过氧化物酶4 (GPX4)；它是哺乳动物中唯一能够还原细胞膜内磷脂氢过氧化物的过氧化物酶。当GPX4活性受损时，脂质过氧化可导致铁凋亡，这是一种氧化铁依赖性的非凋亡细胞死亡形式。下垂铁与退行性疾病有关；例如，铁下垂抑制剂对帕金森病、亨廷顿病和阿尔茨海默病模型具有保护作用。2另一方面，外源性药物诱导的铁下垂对依赖GPX4修复活性的肿瘤细胞具有选择性致死性，这表明诱导铁下垂可能是治疗某些癌症的有益方法。2,3来自不同来源组织的癌细胞已被筛选对铁中毒诱导化合物的敏感性。包括GPX4抑制剂在内的3种铁下垂诱导剂被发现选择性靶向具有间质或其他耐药特征的癌症。与间质状态与耐药相关一致的是，另一项关于持久性癌细胞的研究显示，持久性癌细胞通过休眠状态逃避常规的细胞毒性治疗，然后恢复并导致肿瘤复发，这揭示了对GPX4途径的类似选择性依赖。事实上，GPX4抑制剂是对这种持久性细胞最具选择性致死性的化合物之一。
Cells are dependent on their lipid composition for establishing and modulating membrane structural integrity, morphology, metabolism, and other cellular functions. For example, among the thousands of lipid species that compose eukaryotic cell membranes, the abundance and localization of polyunsaturated fatty acid (PUFA)-containing phospholipids (PUFA-PLs) are major factors in determining the fluidity of cell membranes. 1 Because the cis conformation of double bonds in PUFAs hinders efficient stacking of these fatty acid tails, elevated levels of PUFA-PLs contribute to increasing membrane fluidity and thinning. PUFAs are, however, susceptible to lipid peroxidation via reaction with molecular oxygen at bis-allylic positions, catalyzed by lipoxygenases or through non-enzymatic mechanisms. Oxygenated PUFAs can serve as lipid signals, regulating inflammatory processes, for example. However, peroxy-PUFAs are prone to decompose into reactive species, which can damage biomolecules, such as proteins and nucleic acids. Thus, cells depend on a critical network of proteins to repair PUFA-PL peroxides. A key protein at the center of this repair network is the selenoprotein glutathione peroxidase 4 (GPX4); it is the only peroxidase in mammals capable of reducing phospholipid hydroperoxides within cell membranes. When GPX4 activity is compromised, lipid peroxidation can cause ferroptosis, an oxidative iron-dependent form of nonapoptotic cell death. Ferroptosis has been implicated in degenerative diseases; for example, ferroptosis inhibitors are protective in models of Parkinson, s, Huntington, s and Alzheimer, s diseases. 2 On the other hand, ferroptosis induced by exogenous agents is selectively lethal toward tumor cells that are addicted to GPX4 repair activity, which has suggested that inducing ferroptosis may be a beneficial approach to treating some cancers. 2, 3Cancer cells from tissues of diverse origins have been screened for their sensitivity to ferroptosis-inducing compounds. 3 Ferroptosis inducers, including GPX4 inhibitors, were found to selectively target cancers with a mesenchymal or otherwise drug-resistant signature. Consistent with the mesenchymal state being associated with drug resistance, another study on persister cancer cells, which are proposed to escape from conventional cytotoxic treatment through a dormant state and then revive to cause tumor relapse, revealed a similar selective dependency on the GPX4 pathway. 4 Indeed, GPX4 inhibitors were among the compounds most selectively lethal to such persister cells.
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影响因子：
64.8
作者：
Fischer KR;Durrans A;Lee S;Sheng J;Li F;Wong ST;Choi H;El Rayes T;Ryu S;Troeger J;Schwabe RF;Vahdat LT;Altorki NK;Mittal V;Gao D
通讯作者：
Gao D
影响因子：
64.8
作者：
Viswanathan VS;Ryan MJ;Dhruv HD;Gill S;Eichhoff OM;Seashore-Ludlow B;Kaffenberger SD;Eaton JK;Shimada K;Aguirre AJ;Viswanathan SR;Chattopadhyay S;Tamayo P;Yang WS;Rees MG;Chen S;Boskovic ZV;Javaid S;Huang C;Wu X;Tseng YY;Roider EM;Gao D;Cleary JM;Wolpin BM;Mesirov JP;Haber DA;Engelman JA;Boehm JS;Kotz JD;Hon CS;Chen Y;Hahn WC;Levesque MP;Doench JG;Berens ME;Shamji AF;Clemons PA;Stockwell BR;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
64.8
作者：
Hangauer MJ;Viswanathan VS;Ryan MJ;Bole D;Eaton JK;Matov A;Galeas J;Dhruv HD;Berens ME;Schreiber SL;McCormick F;McManus MT
通讯作者：
McManus MT
影响因子：
64.5
作者：
Stockwell BR;Friedmann Angeli JP;Bayir H;Bush AI;Conrad M;Dixon SJ;Fulda S;Gascón S;Hatzios SK;Kagan VE;Noel K;Jiang X;Linkermann A;Murphy ME;Overholtzer M;Oyagi A;Pagnussat GC;Park J;Ran Q;Rosenfeld CS;Salnikow K;Tang D;Torti FM;Torti SV;Toyokuni S;Woerpel KA;Zhang DD
通讯作者：
Zhang DD
影响因子：
7.8
作者：
Agmon E;Stockwell BR
通讯作者：
Stockwell BR