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Secoisolariciresinol Diglucoside Induces Caspase‐

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Secoisolariciresinol Diglucoside Induces Caspase‐ Received: 13 October 2020 | Revised: 12 March 2021 | Accepted: 21 March 2021 DOI: 10.1111/jfbc.13719 FULL ARTICLE Secoisolariciresinol diglucoside induces caspase- 3- mediated apoptosis in monolayer and spheroid cultures of human colon carcinoma cells Meltem Özgöçmen1 | Dilek Bayram1 | Gülçin Yavuz Türel2 | Vehbi Atahan Toğay2 | Nilüfer Şahin Calapoğlu2 1Department of Histology and Embryology, School of Medicine, Süleyman Demirel Abstract Universtiy, Isparta, Turkey Apoptotic effects of secoisolariciresinol diglucoside (SDG) in 2D and 3D cultures of 2 Department of Medical Biology, School SW480 cells were investigated. 40– 200 M SDG was used and IC50 values were de- of Medicine, Süleyman Demirel Universtiy, μ Isparta, Turkey termined for three different time intervals as 24, 48, or 72 hr for further experiments. BrdU, TUNEL, AIF, and caspase- 3 stainings were used. SDG inhibited cell prolifera- Correspondence Meltem Özgöçmen, Department of tion almost half and half for all time intervals in 2D and 3D cultures and also, induced Histology and Embryology, Faculty of apoptosis. Apoptotic cell percentages in the control group for 24, 48, and 72 hr were Medicine, Süleyman Demirel University, Isparta, Turkey. 27.00%, 29.00%, and 28.00%, respectively, while in the SDG treatment group were Email: [email protected] 59.00%, 61.00%, and 62.00%, respectively. In the spheroid cell culture, apoptotic cell Funding information percentages in the control group for 24, 48, and 72 hr were 6.90%, 7.20%, and 7.10%, Süleyman Demirel University, Grant/Award respectively, while in the SDG treatment group were 19.50%, 19.50%, and 20.70%, Number: 4399 - D2 – 15 respectively. Caspase- 3 and AIF antibodies were used to indicate caspase- dependent and - independent apoptotic pathways. Significant increases were seen in both AIF and caspase- 3 stainings when compared to the control group but caspase- 3 stain- ing results were significantly greater when compared to the AIF staining at all time intervals (p < .05). To prove this, CASP3 gene expression was evaluated by RT- qPCR. Unlike staining results, there was no statistically significant change at 24 hr in 2D and 3D cultures. But, significant upregulation at 48 (2.32- fold in 2D and 2.46- fold in 3D) and 72 hr (5.04- fold in 2D and 6.45- fold in 3D) were seen. Practical applications Colon cancer is one of the most prevalent cancer in the developed countries and its etiology is complex. Although the underlying mechanisms are mostly unknown, the link between diet and colon cancer is known and dietary habits can promote cancer or protect against it. In recent years, flaxseed is accepted as a significant functional food ingredient and feeding with it could help in to prevent cancer. Secoisolariciresinol diglucoside is a flaxseed lignan and is metabolized to mammalian lignans by the gut. In the present study, SDG was evaluated for its apoptotic effects in colon carcinoma cell line via monolayer and spheroid cultures using immunohistochemical and gene expression techniques. Findings of this study suggest that SDG may protect against cancers and in particularly against colon cancer and further investigations has to be carried out for detailed underlying mechanisms. J Food Biochem. 2021;00:e13719. wileyonlinelibrary.com/journal/jfbc © 2021 Wiley Periodicals LLC. | 1 of 10 https://doi.org/10.1111/jfbc.13719 2 of 10 | ÖZGÖÇMEN ET AL. KEYWORDS caspase- 3, colon carcinoma, monolayer culture, secoisolariciresinol diglucoside, spheroid culture, SW480 Highlights • SDG treatment for 100 μM at 24 hr and for 150 μM at 48 and 72 hr significantly reduced the viability of SW480 cells. • SDG- induced apoptosis and inhibited cell proliferation at all time intervals. • Apoptotic cells increased in AIF and caspase- 3 stainings in SDG treatment groups but this increase was significantly greater in the caspase- 3 compared to the AIF. • Relative gene expression of CASP3 was significantly upregulated at 48 and 72 hr in 2D and 3D cultures in a time- dependent manner. 1 | INTRODUCTION 2 | MATERIALS AND METHODS Colon cancer is one of the most common cancer in the developed 2.1 | Cell line, chemicals, and reagents world. Its etiology is complex, but diet is considered to be one of the important reason of it and researchers think that lots of people SW480 (Cat. No: ACC 313, DSMZ GmbH, Germany), RPMI 1640 are at risk of colon cancer because of diet style. The link between (Cat. No: 11875085, Gibco, USA), SDG (CAS no: 148244- 82- 0, Cat diet, especially dietary fiber intakes from whole grains, and colon no: S0202, purity ≥97.0%), Streptomycin (Cat. No: S9137), Penicillin cancer is well established. (Leduc et al., 2017; Pfister et al., 2015; (Cat. No: P3032), PBS, Trypan Blue, Trypsin- EDTA and hydrogen Saura- Calixto, 2011). To struggle colon cancer, patients seek sup- peroxide (Sigma St. Louis, MO, USA), Ethanol, DMSO, Xylol, Mayer's plementary therapies including the use of phytoestrogen- rich foods Hematoxylin Solution, Methyl green, Apop Tag Apoptosis detection (Mali et al., 2017). As a result of this increased awareness in people, kit (Merck KGaA, Germany), 5% heat- inactivated fetal bovine serum the demand for functional and healthy foods is increasing, which (Biological Industries, USA), Active Caspase- 3 polyclonal antibody (Cat. pushes the food industry to increase the production of these foods No: PA1- 26426), AIF polyclonal antibody (Cat. No: PA5- 96166), BrDU (Bernacchia et al., 2014). Staining Kit (Invitrogen, Thermo Fisher Scientific Inc., USA), PureZOL In recent years, flaxseed is accepted as a significant functional RNA Isolation Reagent, iScript Reverse Transcription Supermix, and food. Studies have shown that flaxseed could help to prevent from iTaq Universal SYBR Green Supermix (Bio- Rad Laboratories Inc., USA) diseases like cardiovascular, obesity, and cancer (Imran et al., 2015; were purchased from mentioned companies. Touré & Xueming, 2010). Secoisolariciresinol diglucoside (SDG), a lignan, is abundantly found in flaxseeds. Lignans are similar in structure to the endog- 2.2 | Cell culture enous estrogen, estradiol, and to the estrogenlanti– estrogen, tamoxifen, and appear to act as both anti- estrogens and weak SW480 colon carcinoma cells were cultured as monolayer and sphe- estrogens (Al- Jumaily & Mahdi, 2013; Dietz et al., 2016). SDG roid using RPMI 1640 with 10% FBS, 5% CO2 at 37°C and, 100 U/ is metabolized to enterodiol and enterolactone by the gut ml penicillin and 100 U/ml streptomycin were added. Cells were har- and has protective effects against hormone sensitive cancers vested by detaching with 0.05% trypsin- EDTA then RPMI 1640 was such as breast, prostate, and colon (Al- Jumaily & Mahdi, 2013; added and centrifuged. Maximum of 15 in- house passages were used. Fuentealba et al., 2014; Mali et al., 2017) and is known as phy- Colon spheroid culture was prepared as described in our previous pub- toestrogen because of their potential antioxidant and estro- lication (Bayram et al., 2017). Biological replicates were conducted. genic activity (Ghazanfarpour et al., 2016; Nesbitt, 1999; Patel et al., 2012). Relatively few studies have been done to demonstrate cancer 2.3 | Experimental design and cytotoxicity preventive effects of SDG in in vitro, especially in spheroid cul- 5 ture, SDG was evaluated for its apoptotic effects in colon carci- A total of 5 × 10 cells per well were seeded to 6- well plate and noma cell line (SW480) via monolayer and spheroid cultures using cells were treated with 40 to 200 μM SDG resolved in DMSO for immunohistochemical and gene expression techniques in the pres- three different time intervals as 24, 48, and 72 hr. After incubation, ent study. cytotoxicity was determined by trypan blue and was counted with ÖZGÖÇMEN ET AL. | 3 of 10 a hemacytometer. The effective concentration (IC50) of SDG was 2.7 | Gene expression determined as 100 μM for 24 hr and 150 μM for 48 and 72 hr. Cells were detached using cell scraper and total RNA purification was 7 performed using PureZOL RNA Isolation Reagent from 1 × 10 cells 2.4 | BrdU staining which were treated with 100 μM SDG for 24 hr and 150 μM SDG for 48 and 72 hr. RNA concentration and purity were measured in dupli- DNA synthesis analyses of BrdU Labeling index were used. A total of 1 cate in NanoDrop (Thermo Fisher Scientific, USA). Purity was about 5 × 10 cells per well were seeded to 24- well plate and cells were treated ∼1.9 (OD260/OD280) and RNA integrity was assessed by agarose with 100 or 150 μM SDG according to time intervals on glass cover gel electrophoresis as described here (Çelik et al., 2020). Reverse slips for monolayer cultures. For spheroid culture, spheroids were re- transcription was completed using iScript Reverse Transcription. For moved, fixed, and washed with tap water. Then incubated with ethanol cDNA, 1 µg of RNA was used and synthesized cDNA was diluted series and xylene, embedded in paraffin, and sectioned by microtome 1/20 for each reaction. Triplicate real- time qPCR was performed on and attached to a slide coated with polylysine. Sections were depar- CFX96 Real- Time PCR Detection System (Bio- Rad Laboratories Inc., affinized with xylene and were rehydrated in a series of graded alcohol. USA) with iTaq Universal SYBR Green Supermix. Amplification pa- Remaining procedure was same for both monolayer and spheroid cul- rameters were, 1 cycle: Polymerase Activation & DNA Denaturation tures and described in our previous publication (Bayram et al., 2017). at 95°C for 30 s and 40 cycles: Denaturation at 95°C for 5 s and Annealing/Plate Read at 60°C for 30 s. 2.5 | Apoptosis analysis 2.8 | Statistical analysis TUNEL assay was used for the detection of apoptosis. A total of 1 × 5 10 cells per well were seeded to 24- well plate and treated with 100 p < .05 were considered significant. One- way ANOVA and Dunnett's or 150 μM SDG.
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