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Effective Ferroptotic Small-Cell Lung Cancer Cell Death from SLC7A11 Inhibition by Sulforaphane

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Effective Ferroptotic Small-Cell Lung Cancer Cell Death from SLC7A11 Inhibition by Sulforaphane ONCOLOGY LETTERS 21: 71, 2021 Effective ferroptotic small-cell lung cancer cell death from SLC7A11 inhibition by sulforaphane YUKO IIDA1*, MAYUMI OKAMOTO-KATSUYAMA1*, SHUICHIRO MARUOKA1, KENJI MIZUMURA1, TETSUO SHIMIZU1, SOTARO SHIKANO1, MARI HIKICHI1, MAI TAKAHASHI1, KOTA TSUYA1, SHINICHI OKAMOTO1, TOSHIO INOUE1, YOKO NAKANISHI2, NORIAKI TAKAHASHI1, SHINOBU MASUDA2, SHU HASHIMOTO1,3 and YASUHIRO GON1 1Division of Respiratory Medicine, Department of Internal Medicine; 2Division of Oncologic Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610; 3Shonan University of Medical Science, Kanagawa 244-0806, Japan Received October 20, 2019; Accepted October 14, 2020 DOI: 10.3892/ol.2020.12332 Abstract. Small-cell lung cancer (SCLC) is a highly aggres- lower in SFN-treated cells compared with that in the control sive cancer with poor prognosis, due to a lack of therapeutic cells (P<0.0001 and P=0.0006, respectively). These results targets. Sulforaphane (SFN) is an isothiocyanate derived indicated that the anticancer effects of SFN may be caused from cruciferous vegetables and has shown anticancer effects by ferroptosis in the SCLC cells, which was hypothesized against numerous types of cancer. However, its anticancer to be triggered from the inhibition of mRNA and protein effect against SCLC remains unclear. The present study aimed expression levels of SLC7A11. In conclusion, the present study to demonstrate the anticancer effects of SFN in SCLC cells by demonstrated that SFN-induced cell death was mediated via investigating cell death (ferroptosis, necroptosis and caspase ferroptosis and inhibition of the mRNA and protein expression inhibition). The human SCLC cell lines NCI-H69, NCI-H69AR levels of SLC7A11 in SCLC cells. The anticancer effects of (H69AR) and NCI-H82 and the normal bronchial epithelial SFN may provide novel options for SCLC treatment. cell line, 16HBE14o- were used to determine cell growth and cytotoxicity, evaluate the levels of iron and glutathione, and Introduction quantify lipid peroxidation following treatment with SFN. mRNA expression levels of cystine/glutamate antiporter xCT Small-cell lung cancer (SCLC), which accounted for ~15% of (SLC7A11), a key component of the cysteine/glutamate anti- all cases of lung cancer in the United States in 2020 (1), is a porter, were measured using reverse transcription-quantitative highly aggressive lung cancer tumor. The 5-year survival rate PCR, while the levels of SLC7A11 protein were measured was <7% in the United States in 2017 (2). The survival rate is using western blot analysis. Following the addition of SFN poor for a number of reasons. Firstly, SCLC is characterized to the cell culture, cell growth was significantly inhibited, by rapid growth and metastasis and the lack of early detec- and cell death was shown in SCLC and multidrug-resistant tion means few cases can be treated by surgery (3). Secondly, H69AR cells. The ferroptotic effects of SFN were confirmed the initial effects of chemotherapy quickly diminish, and the following culture with the ferroptosis inhibitor, ferrostatin-1, majority of patients relapse within the first year, worldwide (1), and deferoxamine; iron levels were elevated, which resulted in developing multidrug resistance. Finally, a lack of adequate the accumulation of lipid reactive oxygen species. The mRNA surgical tissues and re-biopsy for molecular profiling results and protein expression levels of SLC7A11 were significantly in few therapeutic options for SCLC compared with that in non-small-cell lung cancer (NSCLC). Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables, particularly broccoli sprouts (4). SFN has been reported to protect against the development of Correspondence to: Dr Shuichiro Maruoka, Division of numerous types of cancer, such as liver, prostate, and colon Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, 30-1 Ohyaguchi-Kamimachi, cancer, by inhibiting phase I enzymes, that activate carcino- Itabashi, Tokyo 173-8610, Japan gens, and by inducing nuclear factor erythroid 2-related E-mail: [email protected] factor 2 (Nrf2)-regulated genes of phase II detoxification enzymes (4-7). The anticancer effects of SFN in various types *Contributed equally of cancer have been reported, in both in vitro and in vivo studies. For example, SFN has been reported to induce apop- Key words: anticancer effect, cell death, ferroptosis, small-cell lung totic cell death in NSCLC, as well as in pancreatic, breast and cancer, sulforaphane prostate cancer (8-11). Other angiogenic activities of SFN are mediated by the suppression of vascular endothelial growth factor and matrix metalloproteinase-2 (12). Antimetastatic 2 IIDA et al: FERROPTOTIC SMALL-CELL LUNG CANCER CELL DEATH BY SULFORAPHANE effects of SFN were also achieved by inhibiting cell migration (Sigma-Aldrich; Merck KGaA), supplemented with 10% FBS and invasion (13,14). However, the anticancer effects of SFN (Sigma-Aldrich; Merck KGaA) and 1% penicillin-streptomycin against SCLC have not yet been fully elucidated. (Nacalai Tesque, Inc.) while, the 16HBE cells were cultured in Ferroptosis is a type of programmed cell death, that is minimum essential medium (Sigma-Aldrich; Merck KGaA) non-apoptotic and has been described as an iron- and reac- supplemented with 10% FBS (Sigma-Aldrich; Merck KGaA) tive oxygen species (ROS)-dependent form of regulated cell and 1% penicillin-streptomycin (Nacalai Tesque, Inc.). The death (15). The morphological features of ferroptotic cells cells were maintained at 37˚C in a humidified atmosphere include alterations in the mitochondrial structure, accom- with 5% CO2. Stocks of these cells were prepared within five panied by the absence of nuclear shrinkage and ruptured passages of receipt; cells used for experiments were passaged plasma membranes (15,16). This process is triggered by two for <6 months. mechanisms. The first mechanism is the inhibition of system xc- (e.g. induced by erastin) (17). System xc- is the cystine/ MTT assay. H69 cells (5,000 cells/well) were treated with glutamate antiporter that imports extracellular cystine in increasing concentrations (1, 5, 10, 20 µM) of SFN and exchange for intracellular glutamate (18). The cystine/gluta- seeded into each well of 96-well plates. Control cells were mate antiporter xCT (SLC7A11) is a key component of system left untreated. Cells were incubated for 24, 48 and 96 h at xc- (19). Intracellular cystine starvation leads to the depletion 37˚C in a humidified atmosphere with 5% CO2. Cell viability of glutathione (GSH) levels and subsequent inactivation of was measured using an MTT Cell Viability Assay kit (cat. GSH peroxidase 4 (GPX4) function (20). The second mecha- no. 30006; Biotium, Inc.). The signal absorbances were nism of ferroptosis is direct blocking of GPX4 [e.g. induced by measured at 570 nm using a Multiskan™ GO Microplate Ras-selective lethal (RSL)3] (21,22). GPX4 is an enzyme that Spectrophotometer (Thermo Fisher Scientific, Inc.) according reduces lipid hydroperoxides to lipid alcohols (15). The loss of to the manufacturer's instructions, and the background absor- GPX4 activity leads to the formation of high lipid ROS (15,22). bance at 630 nm was subtracted. In addition, excessive iron also contributes to ferroptotic cell death by producing ROS via the Fenton reaction (23,24). A Lactate dehydrogenase (LDH) assay. To determine if cell death previous report demonstrated that siramesine and lapatinib was induced by SFN in the H69, H82, H69AR and 16HBE cell induced ferroptosis in breast cancer cells (25). The newly lines, the release of LDH into the medium was measured using discovered ‘ferroptosis’ form of programmed cell death (17) a Cytotoxicity LDH Assay kit-WST (LDH assay) (Dojindo may provide a novel target for cancer treatment. Molecular Technologies, Inc.). The cells were treated with The present study investigated the cell death effects of SFN z-vad (10 µM), necrostatin-1 (50 µM), ferrostatin-1 (1 µM), and treatment and demonstrated the anticancer effects of SFN in DFO (10 µM) 1 h before SFN treatment at 37˚C. Each sample SCLC cells. (5,000 cells/well) treated with SFN was incubated in a 96-well plate for 48 or 96 h at 37˚C, and the LDH assay was performed Materials and methods according to the manufacturer's instructions. H69 and H69AR cells (5,000 cells/well) treated with AMR were incubated Reagents. SFN (R,S-sulforaphane; cat. no. S8044) was in a 96-well plate for 96 h at 37˚C, and the LDH assay was purchased from LKT Laboratories, Inc.. SFN was dissolved performed. The absorbance of each sample was determined at in DMSO and was subsequently used for each assay. Z-vad 490 nm, using a Multiskan GO Microplate Spectrophotometer (cat. no. 4800-520), an apoptosis inhibitor, was purchased from (Thermo Fisher Scientific, Inc.). LDH release (cytotoxicity) was Medical and Biological Laboratories Co., Ltd. Necrostatin-1 calculated by comparing the absorbance with maximum LDH (cat. no. N9037), a necroptosis inhibitor, ferrostatin-1 (cat. release (value measured upon adding the lysis buffer included no. SML0583), a ferroptosis inhibitor, and deferoxamine (DFO; in the kit) of control cells (28). Representative images of the cat. no. D9533), an iron chelator, were purchased from Sigma- H69 cell line undergoing cell death in SFN-treated (20 µM) Aldrich (Merck KGaA). The optimum concentration of each and untreated controls were obtained using Fluorescent Cell reagent
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