Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer

Roh, Jong–Lyel; Kim, Eun Hye; Jang, Hye Jin; Park, Jin Young; Shin, Dong-Ho

doi:10.1016/j.canlet.2016.07.035

Cited by 268 publications

(196 citation statements)

References 36 publications

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“…Nevertheless, whether, miR-372 is involved in autophagy induction, which then modulates the inhibition of apoptosis that results from ZBTB7A targeting, needs further investigation. Ferroptosis has been shown to sensitize HNSCC cells to CDDP treatment (48). However, our preliminary assays did not show a decrease in drug-induced apoptosis following blockage of ferroptosis.…”

Section: Discussioncontrasting

confidence: 67%

The miR-372-ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma

Yeh¹,

Yang

Wu³

et al. 2020

Front. Oncol.

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miR-372 has been shown a potent oncogenic miRNA in the pathogenesis of oral squamous cell carcinoma (OSCC). The zinc finger and BTB domain containing 7A protein (ZBTB7A) is a transcriptional regulator that is involved in a great diversity of physiological and oncogenic regulation. However, the modulation of ZBTB7A in OSCC remains unclear. Tissue analysis identifies a reverse correlation in expression between miR-372 and ZBTB7A in OSCC tumors. When OSCC cells have stable knockdown of ZBTB7A, their oncogenic potential and drug resistance is increased. By way of contrast, such an increase is attenuated by expression of ZBTB7A. Screening and validation confirms that ZBTB7A is able to modulate expression of the death receptors TRAIL-R1, TRAIL-R2, Fas and p53 phosphorylated at serine-15. In addition, ZBTB7A transactivates TRAIL-R2, which sensitizes cells to cisplatin-induced apoptosis. The ZBTB7A-TRAIL-R2 cascade is involved in both the extrinsic and intrinsic cisplatin-induced pathways of apoptosis. Database analysis indicates that the expression level of and the copy status of ZBTB7A and TRAIL-R2 are important survival predictors for head and neck cancers. Collectively, this study indicates the importance of the miR-372-ZBTB7A-TRAIL-R2 axis in mediating OSCC pathogenesis and in controlling OSCC drug resistance. Therefore, silencing miR-372 and/or upregulating ZBTB7A would seem to be promising strategies for enhancing the sensitivity of OSCC to cisplatin therapy.

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Section: Discussioncontrasting

confidence: 67%

The miR-372-ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma

Yeh¹,

Yang

Wu³

et al. 2020

Front. Oncol.

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“…8 The xCT expression alone might be used as a prognostic biomarker in patients with oral cavity SCC, whether tumor cells show CD44 immunopositivity or not. Sulfasalazine, a xCT selective inhibitor, was found to be highly effective against several types of cancer cells 27,30,31 and to selectively trigger apoptosis in CD44v-expressing head and neck SCC cells. 32 Our data suggest that the expression of CD44/xCT has a crucial role in the progression and aggressiveness of tumor cells, and it may be an important clinical marker of response to treatment in patients with oral cavity SCC.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of cysteine‐glutamate transporter and CD44 for prediction of recurrence and survival in patients with oral cavity squamous cell carcinoma

et al. 2018

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Background This study analyzed the expression of CD44 and cystine‐glutamate transporter SLC7A11 (xCT) in primary oral cavity squamous cell carcinoma (SCC) and the relationships of expression to tumor recurrence and patient survival. Methods Associations between CD44 and xCT expression and clinicopathologic results were analyzed in 231 patients with oral cavity SCC. Cox proportional hazard analyses were used to identify factors associated with recurrence‐free survival (RFS), disease‐specific survival (DSS), and overall survival (OS). Results Overexpression of CD44 and/or xCT was associated with advanced T classification, perineural invasion, and lymphovascular invasion (P < .05 each). High expression of xCT was also associated with nodal metastasis and depth of invasion (P < .01 each). Multivariate analysis indicated that high expression of xCT and both xCT and CD44 were independent predictors of poor RFS, DSS, and OS (P < .05 each). Conclusion Overexpression of xCT or xCT plus CD44 may predict posttreatment recurrence and survival in patients with oral cavity SCC.

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“…Our prior study suggested that cisplatin resistance in HNCs can be overcome by the induction of ferroptosis [29]. In addition, artesunate downregulates RAD51 and increases γH2AX formation, which results in sensitizing ovarian cancer cells to cisplatin [20].…”

Section: Introductionmentioning

confidence: 99%

Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis

et al. 2017

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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 abstractOur 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.

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Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer

Cited by 268 publications

References 36 publications

The miR-372-ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma

The miR-372-ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma

Overexpression of cysteine‐glutamate transporter and CD44 for prediction of recurrence and survival in patients with oral cavity squamous cell carcinoma

Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis

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