ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma.
ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma.
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DOI：
10.1016/j.neo.2021.11.002
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Pan M
中科院分区：
文献类型：
--
作者：
Huang W;Chen K;Lu Y;Zhang D;Cheng Y;Li L;Huang W;He G;Liao H;Cai L;Tang Y;Zhao L;Pan M
索拉非尼是治疗晚期肝细胞癌的一线分子靶向药物，降低索拉非尼的耐药性是临床治疗肝癌亟待解决的重要问题。在目前的研究中，我们确定ABCC5是人肝癌细胞获得性索拉非尼耐药的关键调节因子和有希望的治疗靶点。在对索拉非尼耐药的肝癌细胞中，ABCC5的表达被显著诱导，并与不良的临床预后显著相关。下调ABCC5的表达可显著降低索拉非尼对肝癌细胞的耐药性。重要的是，PI3K/AKT/NRF2轴的激活是索拉非尼诱导ABCC5表达的关键。ABCC5通过稳定SLC7A11蛋白抑制铁下垂，增加细胞内谷胱甘肽(GSH)含量，减轻脂质过氧化堆积。此外，ABCC5的抑制增强了索拉非尼的体内外抗癌活性。这些发现证明了一种新的获得性索拉非尼耐药的分子机制，也表明ABCC5是一种新的肝癌细胞铁性下垂的调节因子。
Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), and reducing sorafenib resistance is an important issue to be resolved for the clinical treatment of HCC. In the current study, we identified that ABCC5 is a critical regulator and a promising therapeutic target of acquired sorafenib resistance in human hepatocellular carcinoma cells. The expression of ABCC5 was dramatically induced in sorafenib-resistant HCC cells and was remarkably associated with poor clinical prognoses. The down-regulation of ABCC5 expression could significantly reduce the resistance of sorafenib to HCC cells. Importantly, activation of PI3K/AKT/NRF2 axis was essential for sorafenib to induce ABCC5 expression. ABCC5 increased intracellular glutathione (GSH) and attenuated lipid peroxidation accumulation by stabilizing SLC7A11 protein, which inhibited ferroptosis. Additionally, the inhibition of ABCC5 enhanced the anti-cancer activity of sorafenib in vitro and in vivo. These findings demonstrate a novel molecular mechanism of acquired sorafenib resistance and also suggest that ABCC5 is a new regulator of ferroptosis in HCC cells.
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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
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
基于流式细胞术的测定缺氧/复氧后心肌细胞线粒体膜电位的方法
影响因子：
1.2
作者：
Chen, Guihao;Yang, Yuejin;Gao, Shuo
通讯作者：
Gao, Shuo
影响因子：
11.2
作者：
Liu, Tong;Jiang, Le;Gu, Wei
通讯作者：
Gu, Wei
影响因子：
--
作者：
Adema AD;Floor K;Smid K;Honeywell RJ;Scheffer GL;Jansen G;Peters GJ
通讯作者：
Peters GJ