Effective ferroptotic small-cell lung cancer cell death from SLC7A11 inhibition by sulforaphane

Iida,Yuko; Okamoto-Κatsuyama,Mayumi; Maruoka,Shuichiro; Mizumura,Kenji; Shimizu,Tetsuo; Shikano,Sotaro; Hikichi,Mari; Takahashi,Mai; Tsuya,Kota; Okamoto,Shinichi; Inoue,Toshio; Nakanishi,Yoko; Takahashi,Noriaki; Masuda,Shinobu; Hashimoto,Shu; Gon,Yasuhiro

doi:10.3892/ol.2020.12332

Effective ferroptotic small-cell lung cancer cell death from SLC7A11 inhibition by sulforaphane

Authors:
- Yuko Iida
- Mayumi Okamoto-Κatsuyama
- Shuichiro Maruoka
- Kenji Mizumura
- Tetsuo Shimizu
- Sotaro Shikano
- Mari Hikichi
- Mai Takahashi
- Kota Tsuya
- Shinichi Okamoto
- Toshio Inoue
- Yoko Nakanishi
- Noriaki Takahashi
- Shinobu Masuda
- Shu Hashimoto
- Yasuhiro Gon
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Affiliations: Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan, Division of Oncologic Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
Published online on: November 25, 2020 https://doi.org/10.3892/ol.2020.12332
Article Number: 71
Copyright: © Iida et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Small-cell lung cancer (SCLC) is a highly aggressive cancer with poor prognosis, due to a lack of therapeutic targets. Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables and has shown anticancer effects against numerous types of cancer. However, its anticancer effect against SCLC remains unclear. The present study aimed to demonstrate the anticancer effects of SFN in SCLC cells by investigating cell death (ferroptosis, necroptosis and caspase inhibition). The human SCLC cell lines NCI-H69, NCI-H69AR (H69AR) and NCI-H82 and the normal bronchial epithelial cell line, 16HBE14o- were used to determine cell growth and cytotoxicity, evaluate the levels of iron and glutathione, and quantify lipid peroxidation following treatment with SFN. mRNA expression levels of cystine/glutamate antiporter xCT (SLC7A11), a key component of the cysteine/glutamate antiporter, were measured using reverse transcription-quantitative PCR, while the levels of SLC7A11 protein were measured using western blot analysis. Following the addition of SFN to the cell culture, cell growth was significantly inhibited, and cell death was shown in SCLC and multidrug-resistant H69AR cells. The ferroptotic effects of SFN were confirmed following culture with the ferroptosis inhibitor, ferrostatin-1, and deferoxamine; iron levels were elevated, which resulted in the accumulation of lipid reactive oxygen species. The mRNA and protein expression levels of SLC7A11 were significantly lower in SFN-treated cells compared with that in the control cells (P<0.0001 and P=0.0006, respectively). These results indicated that the anticancer effects of SFN may be caused by ferroptosis in the SCLC cells, which was hypothesized to be triggered from the inhibition of mRNA and protein expression levels of SLC7A11. In conclusion, the present study demonstrated that SFN-induced cell death was mediated via ferroptosis and inhibition of the mRNA and protein expression levels of SLC7A11 in SCLC cells. The anticancer effects of SFN may provide novel options for SCLC treatment.

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