Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis.
Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis.
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DOI：
10.1016/j.redox.2016.12.010
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发表时间：
2017-04
期刊：
影响因子：
11.4
通讯作者：
Shin, Daiha
中科院分区：
文献类型：
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作者：
Roh, Jong-Lyel;Kim, Eun Hye;Jang, Hyejin;Shin, Daiha
青蒿琥酯是一种抗疟疾药物，由于其通过活性氧（ROS）的产生诱导细胞死亡，已被重新用作抗癌药物。然而，调节癌细胞死亡和细胞对青蒿琥酯的抗性的分子机制仍不清楚。我们研究了青蒿琥酯抗肿瘤作用背后的分子机制，以及克服头颈癌（HNC）青蒿琥酯耐药的方法。青蒿琥酯和胡芦巴碱的作用在不同的HNC细胞系中进行了测试，包括三个顺铂耐药的HNC细胞系。通过细胞活力、细胞死亡、谷胱甘肽（GSH）和ROS产生、蛋白质表达和小鼠肿瘤异种移植模型评估这些药物的作用以及对Keap 1、Nrf 2和HO-1的抑制。青蒿琥酯选择性杀伤HNC细胞，而不杀伤正常细胞。青蒿琥酯敏感性相对较低的顺铂耐药的HNC细胞。青蒿琥酯通过降低细胞GSH水平和增加脂质ROS水平诱导HNC细胞铁凋亡。通过与ferrostatin-1和trolox预处理共孵育来阻断这种作用。青蒿琥酯激活HNC细胞中的Nrf 2-抗氧化反应元件（ARE）通路，这有助于抵抗铁凋亡。沉默Keap 1（Nrf 2的负调节因子）降低了HNC细胞对青蒿琥酯的敏感性。Nrf 2基因沉默或胡芦巴碱逆转了Keap 1沉默和顺铂耐药的HNC细胞对青蒿琥酯的铁凋亡抗性。Nrf 2-ARE通路的激活有助于HNC细胞的青蒿琥酯抗性，并且抑制该通路可消除铁凋亡抗性HNC。我们的研究结果显示青蒿琥酯治疗头颈癌（HNC）的有效性和分子机制。青蒿琥酯通过诱导铁依赖性、ROS积累的铁凋亡选择性地杀死HNC细胞，而不杀死正常细胞。然而，由于Nrf 2-抗氧化反应元件（ARE）通路激活，这种作用在某些顺铂耐药HNC中可能是次优的。抑制Nrf 2-ARE通路增加青蒿琥酯敏感性，逆转耐药HNC细胞的铁凋亡抗性。Nrf 2抑制减弱顺铂耐药HNC细胞的青蒿琥酯耐药性青蒿琥酯（Arts）通过诱导铁依赖性ROS介导的铁凋亡选择性杀死HNC，但不杀死正常细胞。然而，Arts增加了Nrf 2的表达，这有助于对铁凋亡的抵抗。因此，Nrf 2的抑制增强了铁凋亡并导致抗性HNC细胞的死亡。青蒿琥酯通过诱导铁凋亡选择性杀伤癌细胞。由于Nrf 2-ARE途径激活，这在一些顺铂耐药HNC中是次优的。Keap 1沉默诱导HNC细胞中Nrf 2活化并降低青蒿琥酯敏感性。Nrf 2-ARE通路的激活有助于HNC细胞对铁凋亡的抵抗。沉默nrf 2或胡芦巴碱增加青蒿琥酯敏感性和逆转铁凋亡抗性。
Artesunate, an anti-malarial drug, has been repurposed as an anticancer drug due to its induction of cell death via reactive oxygen species (ROS) production. However, the molecular mechanisms regulating cancer cell death and the resistance of cells to artesunate remain unclear. We investigated the molecular mechanisms behind the antitumor effects of artesunate and an approach to overcome artesunate resistance in head and neck cancer (HNC). The effects of artesunate and trigonelline were tested in different HNC cell lines, including three cisplatin-resistant HNC cell lines. The effects of these drugs as well as the inhibition of Keap1, Nrf2, and HO-1 were assessed by cell viability, cell death, glutathione (GSH) and ROS production, protein expression, and mouse tumor xenograft models. Artesunate selectively killed HNC cells but not normal cells. The artesunate sensitivity was relatively low in cisplatin-resistant HNC cells. Artesunate induced ferroptosis in HNC cells by decreasing cellular GSH levels and increasing lipid ROS levels. This effect was blocked by co-incubation with ferrostatin-1 and a trolox pretreatment. Artesunate activated the Nrf2–antioxidant response element (ARE) pathway in HNC cells, which contributed to ferroptosis resistance. The silencing of Keap1, a negative regulator of Nrf2, decreased artesunate sensitivity in HNC cells. Nrf2 genetic silencing or trigonelline reversed the ferroptosis resistance of Keap1-silenced and cisplatin-resistant HNC cells to artesunate in vitro and in vivo. Nrf2–ARE pathway activation contributes to the artesunate resistance of HNC cells, and inhibition of this pathway abolishes ferroptosis-resistant HNC. Our results show the effectiveness and molecular mechanism of artesunate treatment on head and neck cancer (HNC). Artesunate selectively killed HNC cells but not normal cells by inducing an iron-dependent, ROS-accumulated ferroptosis. However, this effect may be suboptimal in some cisplatin-resistant HNCs because of Nrf2–antioxidant response element (ARE) pathway activation. Inhibition of the Nrf2–ARE pathway increased artesunate sensitivity and reversed the ferroptosis resistance in resistant HNC cells. Nrf2 inhibition attenuates artesunate resistance in cisplatin-resistance HNC cells. Artesunate (Arts) selectively kills HNCs but not normal cells via the induction of iron-dependent, ROS-mediated ferroptosis. However, Arts increased Nrf2 expression, which contributed to ferroptosis resistance. Thus, suppression of Nrf2 enhances ferroptosis and causes the death of resistant HNC cells. Artesunate selectively killed cancer cells by inducing ferroptosis. This was suboptimal in some cisplatin-resistant HNC because of Nrf2–ARE pathway activation. Keap 1 silencing induced Nrf2 activation and decreased artesunate sensitivity in HNC cells. Activation of the Nrf2–ARE pathway contributed to the ferroptosis resistance of HNC cells. Nrf2 silencing or trigonelline increased artesunate sensitivity and reversed ferroptosis resistance.
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影响因子：
--
作者：
Jeong DE;Song HJ;Lim S;Lee SJ;Lim JE;Nam DH;Joo KM;Jeong BC;Jeon SS;Choi HY;Lee HW
通讯作者：
Lee HW
影响因子：
11.1
作者：
Krishna, Sanjeev;Ganapathi, Senthil;Ster, Irina Chis;Saeed, Mohamed E. M.;Cowan, Matt;Finlayson, Caroline;Kovacsevics, Hajnalka;Jansen, Herwig;Kremsner, Peter G.;Efferth, Thomas;Kumar, Devinder
通讯作者：
Kumar, Devinder
影响因子：
--
作者：
Kast RE;Boockvar JA;Brüning A;Cappello F;Chang WW;Cvek B;Dou QP;Duenas-Gonzalez A;Efferth T;Focosi D;Ghaffari SH;Karpel-Massler G;Ketola K;Khoshnevisan A;Keizman D;Magné N;Marosi C;McDonald K;Muñoz M;Paranjpe A;Pourgholami MH;Sardi I;Sella A;Srivenugopal KS;Tuccori M;Wang W;Wirtz CR;Halatsch ME
通讯作者：
Halatsch ME
影响因子：
5.1
作者：
Cao, Tian-hui;Jin, Song-gen;Zhao, Ming-yan
通讯作者：
Zhao, Ming-yan
影响因子：
4.7
作者：
Beccafico, Sara;Morozzi, Giulio;Sorci, Guglielmo
通讯作者：
Sorci, Guglielmo