Research ArticleExperimental Studies

Potential of Selenium Compounds as New Anticancer Agents for Cholangiocarcinoma

XURUI DAI, SUYANEE THONGCHOT, HASAYA DOKDUANG, WATCHARIN LOILOME, NARONG KHUNTIKEO, ATTAPOL TITAPUN, PITI UNGARREEVITTAYA, PUANGRAT YONGVANIT, ANCHALEE TECHASEN and NISANA NAMWAT
Anticancer Research November 2016, 36 (11) 5981-5988;

Abstract

We examined the in vitro effects of the selenium compounds sodium selenite (Se) and selenomethionine (SeMet) on cholangiocarcima (CCA) cell growth and migration to determine their potential usefulness as anticancer agents. The effect of both compounds on the selenoprotein M level was investigated, as well as the association between the expression level of selenoprotein M and the patients' clinicopathological data. Se and SeMet inhibited CCA cell growth with half-maximal inhibitory concentration values of 1.7-2.1 μM and 18.8-37.9 μM, respectively. Both compounds increased the ratio of B-cell lymphoma 2 (BCL2) to BCL2-associated X (BAX), triggering apoptotic cell death, and inhibited cell migration by reducing the ratio of N-cadherin to E-cadherin, an epithelial–mesenchymal transition marker. In addition, Se and SeMet increased selenoprotein M protein in CCA cells. Low expression of selenoprotein M in CCA tissues was significantly associated with shorter patient survival. In conclusion, selenium may potentially be an alternative anticancer agent that might lead to a better prognosis in patients with CCA.

The term cholangiocarcinoma (CCA) refers to a group of malignancies derived from biliary trees, basically arising from conditions that cause enduring inflammation, injury and reparative biliary epithelial cell proliferation (1). The highest incidence of CCA has been reported from South-East Asia, especially Thailand (2). However, several epidemiological studies have shown that the incidence and mortality rates of CCA are increasing worldwide (3). Surgery represents the only curative treatment for CCA (4), although chemotherapy and radiation therapy play important roles in attempts to control this disease, potentially improving the survival and the quality of life of patients with advanced-stage CCA (5). Nevertheless, the poor response of CCA to treatment highlights the need for increasing efforts to develop new chemotherapies, as well as for understanding the molecular targets in order to improve the effectiveness of treatment.

Selenium, an essential nutritional trace element, is a vital component in selenoproteins, which are important to human health, primarily via antioxidant, anti-inflammatory systems. Selenium compounds are thought to have important anticancer activity and chemopreventive properties (6, 7). In addition to selenium, the involvement of selenoproteins in cancer progression has also been noted (8). Applications of selenium compounds and selenoproteins in the development and progression of several cancer types have been investigated (9-12), however, the role of these molecules in the induction of CCA apoptosis and suppression of migration via the epithelial–mesenchymal transition (EMT) is still largely unknown. In this study, we report the effects of selenium compounds, namely inorganic selenium as sodium selenite (Se), and organic selenium as selenomethionine (SeMet) on CCA cell growth, programmed cell death and migratory ability. The expression of selenoprotein M in CCA tissues was also determined.

Materials and Methods

Cell culture. Human CCA cell lines (KKU-213 and KKU-M214) were obtained from the specimen bank of the Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Thailand. All cell lines were maintained in Ham's F-12 medium (Gibco, Thermo Fisher Scientific, Carlsbad, CA, USA) supplemented with 2 mg/ml NaHCO3, 100 U/ml penicillin, 100 mg/ml streptomycin and 10% (v/v) fetal bovine serum (FBS; Invitrogen, Thermo Fisher Scientific) at 37°C with 5% CO2.

Patients and samples. Human CCA tissues were surgical specimens, taken before other therapies were given, from patients admitted to surgical wards of the Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand. The protocol for the collection and study was approved by the Ethics Committee for Human Research, Khon Kaen University (#HE571283). Sections of paraffin-embedded CCA tissues 4 μm-thick were obtained from the specimen bank of the Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University.

Western blotting. Cells were washed with ice-cold phosphate-buffered saline (PBS) and lysed with cell lysis buffer. Equal amounts of protein were resolved on 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred to a polyvinylidene fluoride membrane. The membrane was blocked with 5% (w/v) skim milk in tris-buffered saline (TBS) at room temperature for 1 h and then incubated with primary antibody: anti-selenoprotein M (Abcam, Cambridge, UK), anti-BAX, anti-BCL2, anti-E-cadherin, anti-N-cadherin (BD Biosciences, San Jose, CA, USA) and anti-β-actin (Abcam) at 4°C overnight. After rinsing the membrane with 0.1% Tween-20 in TBS (TTBS), the membrane was incubated with a horseradish peroxidase conjugated rabbit or mouse IgG at room temperature for 1 h and then rinsed with TTBS. Finally, the membrane was exposed to ECL™ Prime western blotting detection reagent (GE Healthcare UK Ltd., Little Chalfont, Buckinghamshire, UK) for chemiluminescent detection. β-Actin was used as an internal loading control. Each experiment was performed in triplicate.

Cell viability assay. KKU-M213 and KKU-M214 CCA cells (2×103/100 μl) were seeded into 96-well plates and incubated overnight at 37°C with 5% CO2. Sodium selenite (Na2SeO3) (Se) at 0, 5, 10, 15, 20 and 25 μM and L-selenomethionine (SeMet) at 0, 50, 100, 150 and 200 μM (Sigma-Aldrich, St. Louis, MO, USA) were added and cells incubated for 24, 48 and 72 h. A cell proliferation assay was performed using sulforhodamine B (SRB; Sigma-Aldrich) as previously described (13). The concentration of drug required to inhibit cell proliferation by 50% (IC50) was then determined.

Wound-induced migration assay. CCA cell lines were cultured in medium containing 10% FBS at 37°C with 5% CO2 in a 24-well plate until cells were confluent or nearly (>90%) confluent. Cell monolayers were then scratched, and rinsed several times with 1× PBS to remove cell debris. Cells were incubated in medium containing 0-10 μM of Se or 0-100 μM of SeMet for 0 and 48 h. Cell migration in the wound area was monitored and visualized by microscopy and digitally photographed. The distance of the wound area was measured on the images and the migration area was calculated by using the formula: migration area=(area of original wound − area of wound during healing)/area of original wound.

Immunohistochemical staining of CCA tissues. The paraffin-embedded tissue sections were analyzed by immunohistochemical staining for selenoprotein M according to standard protocols. Rabbit-anti-human selenoprotein M (dilution 1:50) was used as a primary antibody for incubation with sections at 4°C overnight. After washing, the sections were incubated with 1:100 peroxidase-conjugated envision secondary antibodies (DAKO, Glostrup, Denmark), and peroxidase activity was visualized with diaminobenzine solution. Hematoxylin was employed for counterstaining. The staining frequency of proteins localized in the cytoplasm of CCA cells in tumor tissues for all areas per slide was semi-quantitatively scored based on the percentage of positive cells as follows: 0%: negative, 1-25%: 1, 26-50%: 2 or 50%: 3. The intensity of protein staining was scored as weak: 1, moderate: 2, or strong: 3. The staining score was calculated by multiplying the intensity and frequency in each case, which were then categorized into two groups: low expression levels were <4 and high expression levels were ≥4 (14).

View this table:
Table I.

Half-maximal inhibitory concentration (IC50) values of sodium selenite (Se) and selenomethionine (SeMet) for cholangiocarcinoma cell lines.

Statistical analysis. Results from cell viability, western blot analysis and the wound-induced migration assay are represented as the mean±SD. Statistical significance was tested by an independent samples t-test and a two-way ANOVA (GraphPad Prism 5 software; GraphPad Software Inc., La Jolla, CA, USA). The association of selenoprotein M with the clinicopathological parameters of patients with CCA was determined by Fisher's exact test using SPSS software version 19.0 (SPSS Inc., Chicago, IL, USA). Patient survival was calculated from the time of surgical resection to death, and the survival curves were constructed according to the Kaplan–Meier method, with differences assessed in a log-rank test. A p-value of less than 0.05 was defined as statistically significant.

Results

Cytotoxic effect of Se and SeMet on CCA cell growth. The SRB assay was used for determining the ability of Se and SeMet to inhibit CCA cell growth. Tumor cells (KKU-M213 and KKU-M214) were treated with different concentrations of Se and SeMet. We demonstrate that Se and SeMet inhibited tumor cell growth in time-dependent manners (Table I). Our results show that at the end of 72 h, Se inhibited KKU-M213 and KKU-M214 cell growth at 11- and 18-fold lower concentrations, respectively, than SeMet.

Se and SeMet induced programmed cell death. The KKU-M213 and KKU-M214 cells were treated with Se or SeMet for 24 h and western blotting was performed to evaluate the expression levels of BAX and BCL2 proteins (Figure 1A and B). Our results show that the ratio of BAX/BCL2 was significantly increased in Se- (Figure 1C) and SeMet (Figure 1D)-treated KKU-M213 and KKU-M214 cells.

Figure 1.
Figure 1.

Effects of sodium selenite (Se) and selenomethionine (SeMet) on induction of apoptosis-related proteins in KKU-M213 and KKU-M214 cells. Western blot analysis shows B-cell lymphoma 2 (BCL2) and BCL2-associated X (BAX) protein expression in CCA cell lines after treatment with Se (A) and SeMet (B) for 24 h. The BAX/BCL2 protein expression ratio was analyzed for (C) Se and SeMet (D) treated CCA cells. Data in C and D represent the mean±SD of protein band intensity of three independent experiments, which were normalized to the intensity of β-actin. *Statistically significantly different from untreated cells at p<0.05.

Se and SeMet suppressed CCA cell migration via change in EMT-related proteins. After the wound was made, cells were treated with Se, or with SeMet and then cultured for 48 h, at which time the wounds of untreated cell layers were closed (Figure 2A-D). As shown in Figure 2E and F, treatment with Se at 10 μM significantly suppressed the migratory ability (91% in KKU-M213 and 97% in KKU-M214 cells) when compared with untreated cells. Figure 2G and H showed that CCA cells treated with SeMet were markedly inhibited in their migratory ability at 100 μM (70% in both KKU-M213 and KKU-M214 cells) when compared to untreated cells. The EMT markers N-cadherin and E-cadherin (15) were determined in CCA cells treated with Se or SeMet using western blotting (Figure 3A and B). The ratio of N-cadherin to E-cadherin was significantly decreased in CCA cells treated with Se (Figure 3C) and SeMet (Figure 3D) at 48 h in a dose-dependent manner when compared with untreated cells.

Se and SeMet induced selenoprotein M expression. KKU-M213 and KKU-M214 cells were treated with Se or SeMet for 24 h and the protein level of selenoprotein M was assessed by western blotting (Figure 4A and B). Expression of selenoprotein M was markedly induced in both CCA cell lines treated with 0.1 μM of Se (Figure 4C) but it was reduced at 1 μM in KKU-M214 cells and 10 μM in KKU-M213 and KKU-M214 cells. Selenoprotein M protein was significantly increased in SeMet-treated CCA cells at 100 μM for KKU-M213 and for KKU-M214 cells at 25, 50 and 100 μM (Figure 4D).

Selenoprotein M protein expression was down-regulated in human CCA tissues. Of the human CCA tissues from 45 patients with intrahepatic CCA, 31 (69%) were from males and 14 (31%) were females. The age of patients ranged from 37 to 74 years (median age=58 years). For all 45 CCA cases, positive immunohistochemical staining of selenoprotein M protein was seen in the tissue sections. Selenoprotein M was positively stained in the cytoplasm of normal biliary ducts surrounding the tumor area (Figure 5A). Low and high expressions of selenoprotein M were found in normal biliary ducts at rates of 33% (15/45) and 67% (30/45), respectively. In cancerous tissues, selenoprotein M was present with low expression (Figure 5B) in 51% (23/45) and high expression (Figure 5C) in 49% (22/45) of cases (t-test, p<0.0001).

Figure 2.
Figure 2.

Effects of sodium selenite (Se) and selenomethionine (SeMet) on the migration of KKU-M213 and KKU-M214 cells. The wound was allowed to heal for 48 h at 37°C. Cells were incubated in medium containing Se (0-10 μM; A and B) or SeMet (0-100 μM; C and D). Bar plots represent the mean±SD of protein band intensity from three independent experiments which were normalized to the intensity of β-actin (E-H). *Statistically significantly different from untreated cells at p<0.05.

Figure 3.
Figure 3.

Effects of sodium selenite (Se) and selenomethionine (SeMet) on proteins related to EMT induction in KKU-M213 and KKU-M214 cells. Western blot analysis showed N-cadherin (N-Cad) and E-cadherin (E-Cad) protein expression in CCA cell lines after treatment with Se (A) and SeMet (B). The N-Cad/E-Cad protein expression ratio was analyzed for Se- (C) and SeMet (D)-treated CCA cells. Data in C and D represent mean±SD of protein band intensity taken from three independent experiments, which were normalized to the intensity of β-actin. *Statistically significantly different from untreated cells at p<0.05.

Figure 4.
Figure 4.

Effects of sodium selenite (Se) and selenomethionine (SeMet) on selenoprotein M (SelM) induction in KKU-M213 and KKU-M214 cells. Western blot analysis showed SelM protein expression in CCA cell lines after treatment with Se (A) and SeMet (B). The relative level of SelM protein expression was analyzed for Se- (C) and SeMet (D)-treated CCA cells. Data in C and D represent the mean±SD of protein band intensities taken from three independent experiments, that were normalized to the intensity of β-actin. *Statistically significantly different from untreated cells at p<0.05.

View this table:
Table II.

Association between tumor selenoprotein M expression and clinicopathological findings.

Fisher's exact test demonstrated that low selenoprotein M expression was associated with shorter patient survival (p=0.025) (Table II). Age, gender, histological type, overall metastasis and lymph node metastasis did not differ significantly between these two groups. The Kaplan–Meier curve showed that patients with CCA with low selenoprotein M expression in tumor tissues had significantly shorter survival than those with high expression (p=0.043, Figure 5D).

Discussion

It has been widely reported that Se and SeMet have potential use in the suppression of cancer cell growth and metastasis in both in vitro and in vivo studies (9). We investigated the inhibitory effects of these chemicals on CCA cell growth and metastasis. From the IC50 values shown in Table I, SeMet is less toxic towards KKU-M213 and for KKU-M214 cells than Se. Our data suggest that Se had higher efficacy than SeMet on the suppression of CCA growth. Se has been reported to suppress prostate cancer cell growth with average IC50 values of 3.5-7.9 μM and it also induced apoptosis (16), whereas SeMet showed less potential in growth suppression than Se with average IC50 values exceeding 300 μM (17). Our results show that Se and SeMet induced apoptotic cell death by increasing the BAX/BCL2 ratio, indicating that both Se and SeMet have the potential to suppress the growth and induce apoptotic cell death of CCA cells.

Figure 5.
Figure 5.

Immunohistochemical staining of selenoprotein M (SelM) in 45 human cholangicarcinoma tissues. SelM stained positively in the cytoplasm of normal biliary ducts (A) and CCA tissues (B and C) (magnification ×200). In CCA tissues, SelM presented as low (B) and high (C) expression. NB, normal bile duct. D: Patients with low SelM expression had a significantly shorter survival than those with high SelM expression (p=0.043, log-rank test).

EMT is a process that leads to major changes in the organization of the cytoskeleton and adherent junctions (15). During EMT, epithelial cells lose cell–cell contact and undergo major alterations in their cytoskeleton, enabling them to acquire a mesenchymal property with increased motility and invasiveness. Several studies suggest that EMT is often activated during cancer invasion and metastasis (18). From this study, we suggest that Se and SeMet have the ability to suppress CCA cell metastasis as demonstrated by our wound-induced cell migration experiment. These two compounds inhibited CCA cell migration by suppressing the protein level of N-cadherin, apparently leading to a disturbance of EMT (15). Our data suggest that Se and SeMet have the potential for use in treating CCA, but further testing in animal models needs to be performed.

Most selenoproteins have a functional role that impacts on chronic diseases, such as cancer, through management of reactive oxygen species, and are present in numerous antioxidant defense systems throughout the body (19). Selenoprotein M is a newly discovered endoplasmic reticulum-resident protein that is highly expressed in the brain, and it was suggested that it might play a suppressive or protective role in the pathology of Alzheimer's disease (20). Up-regulation of selenoprotein M expression was found in hepatocellular carcinoma liver tissues, where its continuing expression was associated with an increased malignancy grade (21). Obviously, selenoprotein M has a protective function in relation to the antioxidant status in vivo (22). Our data revealed that selenoprotein M expression was induced following low-dose treatment with Se or SeMet in both CCA cell lines, suggesting its protective role against oxidative damage. At the high concentration of 10 μM Se, selenoprotein M expression was significantly suppressed and Se inhibited CCA cell growth by apparently triggering apoptotic cell death. In contrast, expression of selenoprotein M protein continued to increase for SeMet treatment up to 100 μM in both CCA cell lines. This might explain why SeMet has less potency than Se as perhaps it plays a protective role rather than a cytotoxic role toward cancer cells.

As far as we are aware of, we have demonstrated for the first time that the expression of selenoprotein M protein in clinical samples of CCA from patients was down-regulated and associated with shorter survival, which was contrary to the previous study in hepatocellular carcinoma (21). Nevertheless, our study is supported by the previous findings in patients with renal cancer that higher tumor grade and tumor stage at diagnosis negatively correlated with lower concentrations of selenoprotein P (a selenium transporter), and total selenium (23). CCA is a type of cancer associated with oxidative damage, and evidence shows that DNA and proteins are damaged in CCA tissues (24, 25). Oxidized proteins such as oxidized alpha-1 antitrypsin, which is an indicator of oxidative damage, is associated with shorter survival of patients with CCA (26). Therefore, a low selenoprotein M expression, indicating poor antioxidant status and being associated with a poor prognosis, might serve as a prognostic indicator in patients with CCA.

In conclusion, the selenium compounds Se and SeMet possess cytotoxic and anti-metastatic capabilities, suggesting that they might be used as anticancer agents. Selenium compounds are inducers of selenoprotein M, indicating that they might be used for improving the antioxidant system, leading to a reduction in the aggressiveness of CCA.

Acknowledgements

This work was supported by the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission, through the Health Cluster (SHeP-GMS) Khon Kaen University to N.N., Mid-Career Grant (RSA5980012), Thailand Research Fund and a grant from Khon Kaen University to N.N.; a grant fund for the M.Sc. program from the Faculty of Medicine, Khon Kaen University, to X.D. The Authors would like to acknowledge Professor Trevor N. Petney, for editing the draft via Publication Clinic KKU, Thailand.

Footnotes

  • Conflicts of Interest

    The Authors declare that no competing interest exists in regard to this study.

  • Received July 28, 2016.
  • Revision received August 11, 2016.
  • Accepted August 18, 2016.

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Potential of Selenium Compounds as New Anticancer Agents for Cholangiocarcinoma
XURUI DAI, SUYANEE THONGCHOT, HASAYA DOKDUANG, WATCHARIN LOILOME, NARONG KHUNTIKEO, ATTAPOL TITAPUN, PITI UNGARREEVITTAYA, PUANGRAT YONGVANIT, ANCHALEE TECHASEN, NISANA NAMWAT
Anticancer Research Nov 2016, 36 (11) 5981-5988;
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