Induction of Human-Lung-Cancer-A549-Cell Apoptosis by 4

Oct 8, 2018 - Overall, we concluded that HPO-DAEE induces A549-cell apoptosis through the ROS–ERK–p38 pathway and, at least in part, the CHOP ...
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Induction of Human-Lung-Cancer-A549-Cell Apoptosis by 4‑Hydroperoxy-2-decenoic Acid Ethyl Ester through Intracellular ROS Accumulation and the Induction of Proapoptotic CHOP Expression Tetsuro Kamiya,*,† Momoko Watanabe,† Hirokazu Hara,† Yukari Mitsugi,‡ Eiji Yamaguchi,‡ Akichika Itoh,‡ and Tetsuo Adachi† J. Agric. Food Chem. Downloaded from pubs.acs.org by UNIV OF CAMBRIDGE on 10/09/18. For personal use only.

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Laboratory of Clinical Pharmaceutics and ‡Laboratory of Pharmaceutical Synthetic Chemistry, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan ABSTRACT: Royal jelly, a natural product secreted by honeybees, contains several fatty acids, such as 10-hydroxy-2-decenoic acid (DE), and shows anti- and pro-apoptotic properties. 4-Hydroperoxy-2-decenoic acid ethyl ester (HPO-DAEE), a DE derivative, exhibits potent antioxidative activity; however, it currently remains unclear whether HPO-DAEE induces cancer-cell death. In the present study, treatment with HPO-DAEE induced human-lung-cancer-A549-cell death (52.7 ± 10.2%) that was accompanied by DNA fragmentation. Moreover, the accumulation of intracellular reactive oxygen species (ROS, 2.38 ± 0.1-fold) and the induction of proapoptotic CCAAT-enhancer-binding-protein-homologous-protein (CHOP) expression (18.4 ± 4.0-fold) were observed in HPO-DAEE-treated cells. HPO-DAEE-elicited CHOP expression and cell death were markedly suppressed by pretreatment with N-acetylcysteine (NAC), an antioxidant, by 2.40 ± 1.57-fold and 5.7 ± 1.6%, respectively. Pretreatment with 4-phenylbutyric acid (PBA), an inhibitor of endoplasmic reticulum stress, also suppressed A549-cell death (38.4 ± 1.1%). Furthermore, we demonstrated the involvement of extracellular-signal-regulated protein kinase (ERK) and p38related signaling in HPO-DAEE-elicited cell-death events. Overall, we concluded that HPO-DAEE induces A549-cell apoptosis through the ROS−ERK−p38 pathway and, at least in part, the CHOP pathway. KEYWORDS: HPO-DAEE, apoptosis, CHOP, ROS, MAPK

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(U0126 and SB203580) were purchased from Wako Pure Chemical (Osaka, Japan). DE was purchased from Nagara Science (Gifu, Japan). Materials. An anti-CHOP mouse monoclonal antibody (#2895), anti-phospho-ERK mouse monoclonal antibody (#9106), anti-ERK rabbit polyclonal antibody (#4695), anti-phospho-p38 rabbit polyclonal antibody (#9215), and anti-p38 rabbit polyclonal antibody (#9212) were purchased from Cell Signaling Technology (Danvers, MA). An anti-GRP78 rabbit polyclonal antibody (sc-13968) was purchased from Santa Cruz Biotechnologies, Inc. (Dallas TX). An anti-actin mouse monoclonal antibody (MAB1501) was purchased from Millipore Company (Billerica, MA). An anti-poly(ADP-ribose) polymer antibody (10H) mouse monoclonal antibody was purchased from Immuno-Biological Laboratories (Fujioka, Japan). 3-(4,5Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), HRP-conjugated anti-rabbit-IgG (A6154) and anti-mouse-IgG (A4416), and Alexa Fluor 488 goat anti-mouse-IgG were purchased from Sigma-Aldrich Company (St. Louis, MO). 5-(and 6)-Carboxy2′,7′-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA) was purchased from Thermo Fisher Scientific (Waltham, MA). 4-Phenylbutyric acid (PBA) was purchased from LKT laboratory (St. Paul, MN). CHOP siRNA (#146321) and negative siRNA were purchased from ThermoFisher Scientific (Waltham, MA). Cell Culture. Human lung-cancer A549 cells were cultured in DMEM containing 10% FCS, 100 U/mL penicillin, and 100 μg/mL

INTRODUCTION Royal jelly (RJ) contains fatty acids such as 10-hydroxy-2-decenoic acid (DE), 10-hydroxy-2-decanoic acid (DA), and sebacic acid (SA) and exhibits antioxidative, anti-inflammatory, and antitumor activities.1−3 We recently reported that 4-hydroperoxy2-decenoic acid ethyl ester (HPO-DAEE), which is a derivative of DE, upregulated the expression of antioxidative enzymes, including heme oxygenase 1 (HO-1), and suppressed oxidativestress-elicited human-neuroblastoma-SH-SY5Y-cell death.4 On the other hand, some gem-dihydroperoxides have been shown to induce human-leukemia-K562-cell apoptosis through the trapping of reactive oxygen species (ROS).5 On the basis of these findings, HPO-DAEE is considered to function as an intracellular redox modulator that exhibits antioxidative and antitumor activities. Endoplasmic reticulum (ER) stress is involved in the progression of some inflammatory diseases, such as type 2 diabetes, and metabolic disorders through pro-apoptotic pathways.6−8 The CCAAT-enhancer-binding-protein-homologous protein (CHOP) is regarded as a key protein that induces apoptosis.9−11 It has been reported that propolis, a natural product made by honeybees, induces breast-cancer-cell death through the induction of CHOP expression.12 However, whether HPO-DAEE induces lung-cancer-cell apoptosis and the involvement of ER stress in this apoptotic process remain unclear.

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Received: August 14, 2018 Revised: September 25, 2018 Accepted: September 27, 2018

MATERIALS AND METHODS

Chemicals. HPO-DAEE (>95%) was synthesized as previously described.13 DA, SA, N-acetylcysteine (NAC), and MAPK inhibitors © XXXX American Chemical Society

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DOI: 10.1021/acs.jafc.8b04424 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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DEVD-p-nitroanilide overnight. After that, the colorimetric intensity at 415 nm was measured. Detection of Poly(ADP-ribose) Polymerase 1 (PARP-1) Activity. PARP-1 activity was determined by the method described in our previous report.14 After A549 cells (2 × 104 cells) were seeded in four-well microplates, the cells were treated with HPO-DAEE for 24 h. After that, the cells were fixed with 4% paraformaldehyde (PFA), permeabilized with 0.1% Triton X-100, and blocked with 3% BSA− PBS. The cells were then incubated for 1 h with an anti-poly(ADPribose) mouse IgG monoclonal antibody (10H, 1:50) diluted with 3% BSA−PBS. After that, they were further incubated for 1 h with Alexa Fluor 488 goat anti-mouse-IgG (1:400) diluted with 3% BSA−PBS. After that, the cells were visualized under a fluorescence microscope (Biozero BZ-9000, Keyence, Osaka, Japan). Assessment of Intracellular ROS Accumulation. A549 cells were seeded on a four-well microplate (2 × 104 cells/well). After treatment with HPO-DAEE, the cells were further incubated with PBS containing 5% PFA and 5 μM carboxy-H2DCFDA for 20 min. After the cells had been washed twice with ice-cold PBS, DCF fluorescence was observed using a BZ-9000. For time-course experiments, cells were seeded on a 60 mm dish (2 × 105 cells/dish). Following the treatment, the cells were stained with carboxy-H2DCFDA. The fluorescence intensity was measured using a FACS-Verse (BD Biosciences, San Jose, CA) with BD cell Quest Pro. Cell-Cycle Analysis. A549 cells (2 × 105 cells) were seeded in 60 mm dish and then treated with HPO-DAEE for 24 h. After the treatment, the cells were washed with PBS and centrifuged (800g for 3 min); this was followed by staining with propidium iodide (PI; Dojindo, Kumamoto, Japan). The PI intensities were analyzed using a FACS-Verse with BD cell Quest Pro. Quantitative Reverse-Transcription−Polymerase-Chain-Reaction (RT-PCR) Analysis. cDNA preparation and quantitative RT-PCR were performed by the methods described previously.15 The primer sequences used in the present study were as follows: CHOP sense, 5′-CCT TCC AGT GTG TGG GAC TT-3′; CHOP antisense,

streptomycin. Cells were cultured in a humidified 5% CO2 incubator at 37 °C. MTT Assay. A549 cells were seeded in a 96-well microplate (2 × 104 cells/well) and then treated with HPO-DAEE for up to 48 h. After treatment, they were further incubated with fresh DMEM containing 0.5 mg/mL MTT for 2 h. Cells were then added to 0.04 N HCl containing isopropanol, and optical density was measured at 570 nm using a microplate reader. DNA Fragmentation. DNA fragmentation was assessed by the methods described in our previous study.12 Briefly, cell lysates were deproteinized by digestion with proteinase K, and then DNA was extracted with a phenol/chloroform/isoamyl alcohol mixture (25:24:1). After precipitation, RNA was digested with RNase. DNA (5 μg) was separated on an agarose gel, stained with ethidium bromide, and photographed. Caspase-3 Activity. Caspase-3 activity in HPO-DAEE-treated A549 cells were measured using an APOCYTO Caspase-3 Colorimetric Assay Kit (Medical & Biological Laboratories, Nagoya, Japan) according to the manufacturer’s instructions. The cells were lysed in lysis buffer and then incubated with the caspase-3 substrate

Figure 1. Chemical structures of compounds.

Figure 2. Induction of A549-cell apoptosis by treatment with HPO-DAEE. A549 cells were treated with the indicated concentrations of HPO-DAEE, DE, DA, or SA for 24 h (A,C−E) or up to 48 h (B). After that, cell viabilities (A,B), DNA fragmentation (C), caspase-3 activation (D), and PARP-1 activation (E) were assessed. *p < 0.05, **p < 0.01 vs vehicle or time (0 h). Scale bars indicate 50 μm. B

DOI: 10.1021/acs.jafc.8b04424 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Figure 3. Involvement of intracellular ROS in HPO-DAEE-elicited A549-cell death. (A,B) A549 cells treated with the indicated concentrations of HPO-DAEE for 6 h (A) or 100 μM HPO-DAEE for the indicated hours (B), after which intracellular ROS accumulation was assessed. *p < 0.05, **p < 0.01 vs vehicle. (C−F) Cells pretreated with 2 mM NAC for 1 h and then treated with 100 μM HPO-DAEE for 24 h, after which cell viabilities (C), cell cycle (D), caspase-3 activation (E), and PARP-1 activation (F) were assessed. **p < 0.01 vs vehicle (Ct); #p < 0.05, ##p < 0.01 vs HPO-DAEE-treated cells. Scale bars indicate 50 μm. 5′-GTG TGT TTT CCT TTT GCC GT-3′; GRP78 sense, 5′-GAA CAT CCT GGT GTT TGA CC-3′; GRP78 antisense, 5′-CCC AGA TGA GTA TCT CCA TT-3′; 18S rRNA sense, 5′-CGG CTA CCA CAT CCA AGG AA-3′; and 18S rRNA antisense, 5′-GCT GGA ATT ACC GCG GCT-3′. Immunoblotting. Whole-cell lysates were prepared as described in our previous study.16 Protein (20 μg) was boiled with SDS buffer and separated by SDS-PAGE; this was followed by transfer onto PVDF membranes. These membranes were then incubated with primary antibodies against CHOP (1:1000), GRP78 (1:1000), phosphoERK (1:1000), phospho-p38 (1:1000), ERK (1:1000), p38 (1:1000), or actin (1:5000), which was followed by incubation with HRP-conjugated goat anti-rabbit-IgG (1:5000) or anti-mouse-IgG (1:5000). Bands were detected using ImmunoStarLD and imaged using an LAS-3000 UV mini (Fuji Film, Tokyo, Japan). siRNA Transfection. A549 cells were grown in 60 mm dishes and transiently transfected with 50 nM CHOP-specific or negative siRNA using Lipofectamine RNAiMAX Transfection Reagent (Invitrogen) according to the manufacturer’s instructions. Twenty-four hours after transfection, cells were used in some experiments. Statistical Analysis. Data are expressed as the means ± SE of three independent experiments. Statistical analyses on data were

performed using ANOVA followed by post hoc Bonferroni tests. A p-value less than 0.05 was considered to be significant.

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RESULTS AND DISCUSSION RJ contains some fatty acids, such as DE, DA, and SA, and it exerts several bioactive effects, such as antidepressive and antiinflammatory activities and epigenetic gene regulation.17−19 Our recent findings revealed that HPO-DAEE exerted potent antioxidative effects through the induction of HO-1.4 On the other hand, some compounds with a hydroperoxy group induce K562-leukemic-cell apoptosis through the modulation of intracellular redox conditions.5 It currently remains unclear whether HPO-DAEE induces lung-cancer-cell apoptosis, and the underlying molecular mechanisms involved in this apoptosis have yet to be elucidated. Accordingly, we initially investigated whether treatment with RJ derivatives or HPO-DAEE (Figure 1) induces A549-cell injury. Treatment with HPO-DAEE significantly decreased A549-cell viability in a dose-dependent manner, whereas the treatment with 100 μM DE, DA, or SA did not result in A549-cell cytotoxicity (Figure 2A). Moreover, C

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Figure 4. Induction of CHOP expression in A549 cells by treatment with HPO-DAEE. (A) Quantitative RT-PCR results from A549 cells treated with the indicated concentrations of HPO-DAEE for 6 h (left) or 100 μM HPO-DAEE for the indicated hours (right). (B) Immunoblots from cells treated with the indicated concentrations of HPO-DAEE for 6 h. (C) Quantitative RT-PCR results from cells treated with 100 μM HPO-DAEE (HPO), DE, DA, or SA for 6 h. (D,E) Cells pretreated with 0.5 mM PBA or 2 mM NAC or transfected for 1 or 24 h with CHOP siRNA, treated with 100 μM HPO-DAEE for 6 h (D) or 24 h (E), and then analyzed by quantitative RT-PCR (D) or an MTT assay (E). Quantitative RT-PCR data were normalized using 18S rRNA levels. *p < 0.05, **p < 0.01 vs vehicle (Ct) or time (0 h); #p < 0.05, ##p < 0.01 vs HPO-DAEE-treated cells.

our previous report indicated that treatment with 100 μM HPO-DAEE induced the antioxidant enzyme superoxide dismutase 3 (SOD3) in human monocytic THP-1 cells.13 On the basis of these findings, it is considered that the cytotoxic effects of HPO-DAEE may be specific for solid tumor cells. Intracellular ROS-related signaling is known to induce cell apoptosis. Moreover, we previously reported that HPO-DAEE generates intracellular ROS and activates several signaling pathways.4 Therefore, intracellular ROS accumulation was

treatment with HPO-DAEE decreased A549-cell viability in a time-dependent manner (Figure 2B). Additionally, significant DNA fragmentation (Figure 2C), caspase-3 activation (Figure 2D), and PARP-1 activation (Figure 2E) were observed in 100 μM HPO-DAEE-treated cells, indicating that treatment with HPO-DAEE induces A549-cell apoptosis. We also determined a cytotoxic effect of HPO-DAEE in human prostatecancer PC3 cells, and treatment with 100 μM HPO-DAEE induced PC3-cell death (data not shown). On the other hand, D

DOI: 10.1021/acs.jafc.8b04424 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Figure 5. Involvement of MAPK in HPO-DAEE-elicited A549-cell death. (A) Immunoblots of A549 cells treated with 100 μM HPO-DAEE for the indicated times. (B) Immunoblots of cells pretreated with 2 mM NAC for 1 h and then treated with 100 μM HPO-DAEE for 30 min. Relative values of immunoblotting data are described under each blot. (C,D) Cells pretreated with 10 μM U0126 (U) or SB203580 (SB) for 30 min, treated with 100 μM HPO-DAEE for 6 h (C) or 24 h (D), and then analyzed by quantitative RT-PCR (C) or an MTT assay (D). Quantitative RT-PCR data were normalized using 18S rRNA levels. *p < 0.05, **p < 0.01 vs vehicle (Ct) or time (0 h); #p < 0.05, ##p < 0.01 vs HPO-DAEE-treated cells.

assessed in HPO-DAEE-treated A549 cells. DCF fluorescence was slightly observed in basal A549 cells, whereas its fluorescence intensity was significantly enhanced in HPODAEE-treated cells (Figure 3A,B). According to these observations, we further investigated the involvement of ROS in HPO-DAEE-triggered A549-cell apoptosis. As shown in Figure 3C, pretreatment with NAC, a potent antioxidant, completely blocked HPO-DAEE-triggered A549-cell death. Moreover, the induction of a sub-G1 population, an apoptotic population (Figure 3D); caspase-3 activation (Figure 3E); and PARP-1 activation (Figure 3F) were suppressed in the presence of NAC, indicating that HPO-DAEE-elicited

intracellular ROS accumulation plays a critical role in cell death. We previously reported that some natural products, including propolis, induce cancer-cell death through ER-stress pathways.12 In order to cope with ER stress, cells activate some signal pathways that are regulated by inositol-requiring protein 1, PKR-like ER kinase (PERK), or activating transcription factor 6 (ATF6).20 We previously demonstrated that treatment with HPO-DAEE activated the PERK pathways and induced ATF4 expression in human neuroblastoma SH-SY5Y cells.4 ATF4 is known to induce proapoptotic CHOP expression and facilitates apoptotic cascades;21,22 therefore, we investigated E

DOI: 10.1021/acs.jafc.8b04424 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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whether treatment with HPO-DAEE induces ER stress. As shown in Figure 4A, treatment with HPO-DAEE markedly increased the expression of CHOP mRNA in dose- and timedependent manners. Moreover, the induction of CHOP protein was observed in 100 μM HPO-DAEE-treated A549 cells (Figure 4B). The ER-related chaperone, GRP78, was induced in HPO-DAEE-treated cells as well (Figure 4A,B). However, CHOP-mRNA induction was not observed in DE-, DA-, or SA-treated cells (Figure 4C), suggesting that CHOP might play an important role in HPO-DAEE-elicited A549-cell death. Intracellular ROS-related signaling is known to induce ER stress.23−26 In this study, pretreatment with NAC suppressed HPO-DAEE-elicited CHOP induction (Figure 4D), indicating that HPO-DAEE-elicited intracellular ROS activates ER stress. However, as shown in Figure 4D,E, the inhibitory effects of PBA and CHOP siRNA on HPO-DAEE-elicited cell death were weaker than that of NAC. Although ROS-mediated ER stress is not a key driver for apoptosis, it, at least in part, is involved in HPO-DAEE-triggered A549-cell death. We further investigated the signaling pathways involved in HPO-DAEE-elicited cell death. MAPKs, including p38, ERK, and JNK, participate in cell proliferation, differentiation, and death.27−30 ERK pathways have been shown to function as key signals in HPO-DAEE-elicited SOD3 expression in THP-1 cells.13 Accordingly, we investigated whether MAPKs are involved in HPO-DAEE-elicited cell death and CHOP induction. Treatment with HPO-DAEE increased phosphorylated ERK and p38 levels (Figure 5A); however, phosphorylated JNK was not observed (data not shown). Moreover, these increases were suppressed by pretreatment with NAC (Figure 5B), indicating that intracellular ROS activates the ERK- and p38signaling pathways. Furthermore, HPO-DAEE-elicited CHOP induction and A549-cell death were significantly inhibited by pretreatment with U0126, an inhibitor of ERK, and by SB203580, an inhibitor of p38 (Figure 5C,D), suggesting that the p38- and ERK-signaling pathways play a key role in HPODAEE-triggered A549-cell death. In the present study, we investigated whether HPO-DAEE induces apoptosis in A549 cells and revealed for the first time that this apoptosis was, at least in part, mediated by ER-stressrelated pathways. Moreover, intracellular ROS accumulation induced by HPO-DAEE plays a critical role in HPO-DAEEelicited ER stress and cell death. We recently reported that 10 to 50 μM HPO-DAEE induced HO-1 expression and showed the cytoprotective effect in SH-SY5Y cells.4 In fact, treatment with HPO-DAEE at low concentrations induced HO-1 expression in A549 cells as well (data not shown), suggesting that relatively high concentrations of HPO-DAEE may be required for cancer therapy. Previous reports have shown that mice treated with 30 mmol/kg DA via gastric gavage have increased plasma concentrations up to 300 μM.31,32 These results suggest that HPO-DAEE is present in appreciable amounts in peripheral plasma after gastric gavage (10 mmol/kg). However, additional experiments and modifications of the chemical structure of HPO-DAEE are necessary for its clinical application. Although the relationship between the ERK and p38 pathways in HPODAEE-elicited cell death currently remains unclear, our results may contribute to the development of novel anticancer drugs.

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Tetsuro Kamiya: 0000-0002-6650-2981 Eiji Yamaguchi: 0000-0002-1167-8832 Akichika Itoh: 0000-0003-3769-7406 Funding

This study was supported in part by JSPS KAKENHI (to T.K., Grant Numbers 26460070 and 17K08277) and by a grant from Api Company, Ltd. (to H.H.). Notes

The authors declare no competing financial interest.

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ABBREVIATIONS USED DE, 10-hydroxy-2-decenoic acid; HPO-DAEE, 4-hydroperoxy2-decenoic acid ethyl ester; CHOP, CCAAT-enhancer-binding-protein-homologous protein; PBA, 4-phenylbutyric acid; ERK, extracellular-signal-regulated protein kinase; RJ, royal jelly; DA, 10-hydroxy-2-decenoic acid; SA, sebacic acid; HO-1, heme oxygenase 1; ROS, reactive oxygen species; ER, endoplasmic reticulum; NAC, N-acetylcysteine; GRP78, glucose-regulated protein of 78 kDa; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; carboxyH2DCFDA, 5-(and 6)-carboxy-2′,7′-dichlorodihydrofluorescein diacetate; DMEM, Dulbecco’s modified Eagle’s medium; FCS, fetal-calf serum; RT-PCR, reverse transcription−polymerase chain reaction; PARP-1, poly(ADP-ribose) polymerase 1; SOD, superoxide dismutase; PERK, PKR-like ER kinase; ATF, activating transcription factor

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DOI: 10.1021/acs.jafc.8b04424 J. Agric. Food Chem. XXXX, XXX, XXX−XXX