Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis
| Autor: | Hyejin Jang, Daiha Shin, Jong-Lyel Roh, Eun Hye Kim |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine HNC head and neck cancer Resistance Clinical Biochemistry Artesunate Apoptosis Phenylenediamines Biochemistry Mice chemistry.chemical_compound GSH glutathione Head and neck cancer lcsh:QH301-705.5 siRNA short interfering RNA chemistry.chemical_classification Cyclohexylamines Mice Inbred BALB C lcsh:R5-920 Kelch-Like ECH-Associated Protein 1 HO-1 heme oxygenase 1 (HMOX1) Artensunate Artemisinins Gene Expression Regulation Neoplastic Head and Neck Neoplasms shRNA short hairpin RNA lcsh:Medicine (General) Signal Transduction Research Paper TrxR thioredoxin reductase Programmed cell death NF-E2-Related Factor 2 Iron Mice Nude Antineoplastic Agents ARE antioxidant response element MTT 3-[4]-2 5-diphenyl-2H-tetrazolium bromide Nrf2 Antimalarials 03 medical and health sciences Alkaloids Keap 1 Kelch-like ECH-associated protein 1 ROS reactive oxygen species Animals Humans Ferroptosis Viability assay Chromans DCF-DA 2ʹ 7ʹ-dichlorofluorescein diacetate Reactive oxygen species Organic Chemistry Drug Repositioning Membrane Proteins Glutathione Reactive oxygenspecies Xenograft Model Antitumor Assays KEAP1 030104 developmental biology lcsh:Biology (General) chemistry Drug Resistance Neoplasm Cell culture Cancer cell Cancer research Cisplatin Nrf2 nuclear factor erythroid-derived 2-like 2 (NFE2L2) Heme Oxygenase-1 |
| Zdroj: | Redox Biology, Vol 11, Iss, Pp 254-262 (2017) Redox Biology REDOX BIOLOGY(11) |
| ISSN: | 2213-2317 |
| Popis: | 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. Condensed abstract 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. Graphical abstract 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.fx1 Highlights • 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. |
| Databáze: | OpenAIRE |
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