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Year : 2015  |  Volume : 11  |  Issue : 4  |  Page : 840-845

Se-methylselenocysteine suppresses the growth of prostate cancer cell DU145 through connexin 43-induced apoptosis

1 Department of Oncology, Clinical College of Weifang Medical University, Weifang 261031, China
2 Department of Urology, The People's Hospital of Dongying City, Dongying, China
3 Department of Urology, The People's Hospital of Weifang City, Weifang, China

Date of Web Publication15-Feb-2016

Correspondence Address:
Li Qi
Department of Oncology, Clinical College of Weifang Medical University, 465# Yuhe Road, Weifang 261031
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.139265

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 > Abstract 

Context: Se-methylselenocysteine (MSC), as a chemopreventive agent, shows antitumor effects in some cancer models, but its mechanism is still unclear.
Aims: This study is to explore whether MSC induces apoptosis in prostate cancer (PCa) cells DU145 through connexin 43 (Cx43) activation.
Settings and Design: The experiment was performed in a PCa cell line model DU145 and using a series of biological assay methods to investigate the regulating pathway from MSC through Cx43 to downstream molecules, demonstrating an important role of Cx43 in PCa development and as a potential treatment target.
Materials and Methods: The human PCa cell line DU145 was used as a model. The effects of MSC on Cx43 expression were examined by reverse transcription-polymerase chain reaction, western blot; effects on cell growth and proliferation were determined by WST-1 and colony formation assay; small interfering ribonucleic acid was used to evaluate the direct contribution of Cx43 to cancer cell apoptosis.
Statistical Analysis Used: Student's t-test was used to calculate the difference between the groups in SPSS software.
Results: Results showed that MSC inhibited the growth and colony formation of the DU145 cells; MSC induced cell apoptosis by increasing Cx43 expression at messenger ribonucleic acid and protein levels; MSC decreased B-cell lymphoma-2 (Bcl-2) and increased bad levels of DU145 cells.
Conclusions: As a conclusion, MSC exerts pro-apoptosis effects through increasing Cx43 expression, which in turn down-regulates Bcl-2 and up-regulates bad expression.

Keywords: Apoptosis, connexin 43, prostate cancer, Se-methylselenocysteine

How to cite this article:
Lu Z, Qi L, Li Gx, Bo XJ, Liu GD, Wang JM. Se-methylselenocysteine suppresses the growth of prostate cancer cell DU145 through connexin 43-induced apoptosis. J Can Res Ther 2015;11:840-5

How to cite this URL:
Lu Z, Qi L, Li Gx, Bo XJ, Liu GD, Wang JM. Se-methylselenocysteine suppresses the growth of prostate cancer cell DU145 through connexin 43-induced apoptosis. J Can Res Ther [serial online] 2015 [cited 2019 Sep 21];11:840-5. Available from: http://www.cancerjournal.net/text.asp?2015/11/4/840/139265

 > Introduction Top

Prostate cancer (PCa) is a growing public health problem worldwide; it is the fifth most common incident cancer in the world. One in six American men will be diagnosed in their lifetime with PCa, which is the second leading cause of male cancer death in United States. [1] The incidence of PCa is also rising each year in China and more than 30,000 men are diagnosed with PCa every year. [2] Treatment options by hormone ablation therapy, radiation, and surgery for advanced PCa do not offer cure, but only delay the inevitable recurrence of the lethal hormone-refractory disease. Therefore, understanding that how PCa can be prevented is a high priority.

The studies focusing on the relationship between selenium and cancer presumed that selenium exerts its effects as an antioxidant. [3] As a component of glutathione peroxidase, selenium is widely recognized as a player functioning to remove reactive oxygen species. [3] Recent studies have shown clues that selenium-containing compounds are active in mediating cancerous phenotypes. [4] Lee et al. have reported that Se-methylselenocysteine (MSC), one of the selenium-contain compound in natural organic body, was able to potentiate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in renal cancer cells. [5] Yin et al. showed that MSC enhanced the sensitivity of in vivo tumor model to irinotecan by down-regulating the expression of cyclooxygenase-2, inducible nitric oxide synthesis and hypoxia-inducing factor-1 alpha. [6] Clinical trial data also revealed evidence that selenium supplementation can significantly reduce the incidence of PCa in humans. [7] In addition, prospective cohort studies, epidemiological studies and animal tumor models showed inverse relationships between selenium status and cancer incidence. [8],[9]

Connexins, or gap junction proteins, are a family of structurally-related transmembrane proteins that assemble to form vertebrate gap junctions. [10] Mutations in connexin-encoding genes can lead to functional and developmental abnormalities. Studies showed that connexin 43 (Cx43) was closely associated with malignant behaviors of cancer. [11] Altered expression of CxS43 impaired intercellular communication through of gap junction in PCa cells. [12] Combination of nonviral CxS43 gene therapy and docetaxel inhibited the growth of human PCa in mice model. [13] Expressing CxS43 in breast cancer cells reduces their metastasis to lungs. [14]

In the current study, we found that MSC inhibited PCa cell growth and induced cancer cell apoptosis at least partially through CxS43.

 > Materials and methods Top

Chemical reagents

The MSC was purchased from Aldrich-Sigma Company (Shanghai, China). The reverse transcription-polymerase chain reaction (RT-PCR) reagents were achieved from Promega Company (Beijing, China). The primary antibodies of CxS43, B-cell lymphoma-2 (Bcl-2) and bad were purchased from Santa Cruz (California, USA). The secondary antibodies were purchased from Zhong Shan Jin Qiao Biotech Co. (Beijing, China). The CxS43-specific small interfering ribonucleic acid (siRNA) sequence and control sequence were synthesized by Genepharma (Shanghai, China). The siRNA sequence for CxS43 was referred to the previous report [15] : The sense sequence of CxS43 siRNA is 5´-CAAUUCCUCGUGCCGCAATT-3´, and the antisense sequence is 5´-UUGCGGCACGAGGAAUUGTT-3´. The sense sequence of control siRNA is 5´-AAUUCUCCGAACGUGUCACGT-3´, and the antisense sequence is 5´-GUGACACGUUCGGAGAAUUTT-3´.

Cell culture and transfection

Prostate cancer cell line DU145 was kept in our laboratory and was maintained in RPMI-1640 medium complemented with 10% fetal bovine serum (FBS) plus L-glutamine (4 mM), penicillin (100 units/ml), streptomycin (100 lg/ml) at 37°C and 5% CO 2 . The CxS43 coding sequence was cloned into pc deoxyribonucleic acid (DNA) 3.1 (+) vector with KpnI and NotI and was used for stable transfection into DU145 cells. The transfected DU145 cells were selected with medium containing G418 at 400 nmol. The transfection of CxS43 siRNA was performed according to the manufacturer's instructions.

WST-1 assay for cell growth

The growth of DU145 cells after MSC treatment was determined with WST-1 kit (Roche, HK). The cells were planted into a 96-well plate with 10,000 cells/well in 100 μl FBS- complemented culture medium and incubated in CO 2 incubator overnight. The next day, MSC was added into the wells at various concentrations (5, 10, 25, and 100 μmol). After incubation for 24, 48, and 72 h, WST-1 assay reagents were added into the cells, respectively (10 μl/well). Then the cells were incubated for 2 h at 37°C. The plates were read by spectrophotometer at 490 nm.

Colony formation assay

To evaluate the colony formation ability of DU145 cells after MSC treatment, 1000 DU145 cells were seeded into a 10 cm-diameter culture dishes before treatment. The cells were cultured overnight before 5, 10, 25, and 100 μmol of MSC was added into the cells. Then the cells in dishes were cultured for 10 days. At the end of this experiment, colonies with more than 50 cells were counted under an inverted microscope and the numbers of the colonies were plotted. For soft agar assay, respectively treated DU145 cells were seeded in triplicates in 60-mm plates with a top layer of 0.3% agar and a bottom layer of 0.5% agar. Every other day, 0.4 ml medium was supplemented, and the plates were examined microscopically at the end of 2 weeks' culture.

Reverse transcriptase-polymerase chain reaction

Total RNA was isolated from diversely treated DU145 cells with trizol reagent (Cat. 15596, Invitrogen, USA) according to the manufacturer's instructions. Total RNA (6 μg) was reversely-transcribed and treated with RNase-free DNase to avoid contamination from adenovirus genome as described in the instructions (Cat. M6101, Promega, USA). One microliter of cDNA solution was then used as the template for PCR amplification in a 15-μl volume. Sequences of the RT-PCR primers for CxS43 were: forward, 5'- GATGAGGAAGGAAGAGAAGC-3'; reverse, 5'- TTGTTTCTGTCACCAGTAAC-3'. The product is 588 bp in length. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was chosen as the internal standard for quantificational purpose, since GAPDH showed constant expression in various conditions. The ratio of CxS43 signal to GAPDH signal was used as a measurement of the relative abundance of CxS43 expression. The sense primer for GAPDH was 5´-TCCCTCAAGATTGTCAGCAA-3´, and the antisense primer was 5´-AGATCCACAACGGATACATT-3´´. The product of GAPDH amplification is 309 bp in length. PCR was initiated by 5 min incubation at 94°C, followed by 28 cycles of 95°C for 2 min, 60°C for 30 s and 72°C for 30 s. After a final extension at 72°C for 7 min, the reaction mixture was kept at −20°C before undergoing electrophoresis on agarose gel.

Immunoblot detection for protein expression

Whole-cell protein extracts were prepared and quantified by the Bicinchoninic Acid Protein Assay Kit (Pierce, Rockford, IL, USA). Proteins (100 μg/lane) were denatured, resolved on 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels and semi-dry transferred (Bio-Rad) at 12 V for 3 h onto nitrocellulose membranes (Bio-Rad, USA). The membranes were probed with primary antibodies against CxS43 (sc-9059, Santa cruz, USA), Bcl-2 (sc-509, Santa cruz, USA), bad (sc-8044, Santa cruz, USA), PARP , sc-7150, Santa cruz, USA, beta-actin (sc-47778, Santa cruz, USA, or tubulin (sc-8035, Santa cluz, USA) (as a control) overnight at 4°C, followed by incubation with secondary antibody IgG conjugated to horseradish peroxidase and detection using SuperSignal ECL (Applygen Technologic Inc., Peking, China).

Flow cytometry assay for apoptosis

In order to assess the apoptosis, cells were collected (attached and floating) after MSC treatment for 72 h and fixed with 70% ethanol at 4°C overnight. After two washes with phosphate buffered saline (PBS), the cells were incubated in RNase A/PBS (100 μg/ml) at 37°C for 30 min. Intracellular DNA was labeled with propidium iodide (50 μg/ml) and analyzed with a FACSCalibur fluorescence-activated cell sorter (FACS) using CELLQuest software (Becton Dickinson, NJ, USA). The percentages of sub-G1 nuclei in each population were determined from at least 1 × 10 4 cells.


deoxyribonucleic acid fragmentation assay

The DNA fragmentation during MSC-induced apoptosis was measured on agarose gel. Briefly, the cells treated with MSC variously were collected, and DNA was extracted routinely. The DNA was measured for concentration and 2 μg DNA was loaded for agarose gel electrophoresis.

Statistical analysis

The data were analyzed using SPSS software (SPSS 13.0, SPSS, USA). Student's t-test was used to compare the difference between the control and MSC-treated cells. P <0.05 was considered as significant.

 > Results Top

Se-methylselenocysteine inhibited the growth and proliferation of DU145 cells

Considering the effects of MSC on the phenotypes of PCa cells, first we evaluated the inhibition of MSC on the growth and proliferation of DU145 cells. There was a significant inhibition of MSC treatment on the growth of DU145 cells in a dose-dependent and time-dependent manner. At 100 μmol concentration, the growth inhibition rates of MSC were 22.1% and 77.2% at 24 and 72 h after treatment, respectively [Figure 1].
Figure 1: Se-methylselenocysteine (MSC) inhibited the growth and proliferation on DU145 cells. (a) DU145 cells were treated with vehicle control and MSC of various concentrations (5, 10, 25, and 100 μmol) for 24, 48, and 72 h. After that, survived cell were assessed by WST-1 array. (b) DU145 cells were cultured in the media containing various MSC concentrations (5, 10, 25, and 100 ìmol). After incubation for 10 days, colonies with more than 50 cells were counted under an inverted microscope

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For the colony formation assay, 1000 cells were seeded into plates and treated with MSC at different concentrations (5, 10, 25 and 100 μmol). Ten days later, there were fewer colonies in the group of cells at higher MSC concentration. The inhibition was significant at 10 μmol MSC concentration compared with the control group and 5 μmol MSC treated group. At 100 μmol, the colony number was only 26.7% of that of the control group [Figure 1]. Colony formation assay in soft agar confirmed the similar results [Figure 1]c]. These results indicated that MSC exerted effective inhibition on the growth and colony formation of PCa cell DU145.

Effect of Se-methylselenocysteine on apoptosis

To investigate whether the growth inhibition of PCa cells by MSC was associated with apoptosis, we performed flow cytometry assay to detect the apoptotic cells after MSC treatment. Comparing with control, which displayed apoptosis only in 4.7% of the cells, MSC induced significant apoptosis in DU145 cells. With the increase of MSC concentration, higher percentage of apoptotic cells was recorded. At the concentration of 25 μmol, MSC induced apoptosis in 40.2% of the DU145 cells [Figure 2]a], which was consistent with DNA fragmentation assay [Figure 2]b].
Figure 2: Effect of Se-methylselenocysteine (MSC) on DU145 cells to induce apoptosis and expression of connexin 43 (Cx43). (a) MSC induced apoptosis in DU145 cells in a dose-dependent manner. Increasing percentage of apoptosis in the cell line was observed with increase of concentration of MSC treatment; (b) Deoxyribonucleic acid (DNA) samples from DU145 cells treated with MSC were collected and electrophoresed on gel to show the fragmented DNA; (c) Total ribonucleic acid (RNA) was isolated from the cells treat with different concentration of MSC and the gene expression was assessed by reverse transcription-polymerase chain reaction. Results of the Cx43 messenger RNA expression of the cells treated with different concentrations of MSC for 48 h; lysate from the cells with different treatments and the protein expression of Cx43 was assessed by Western blot. Samples were achieved from cells with different concentrations of MSC treatment for 48 h

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Se-methylselenocysteine induced connexin 43 messenger ribonucleic acid and protein expression

It was reported that CxS43 played roles in PCa development. We here determined whether MSC treatment altered CxS43 expression. We performed reverse transcriptase PCR and Western blot to assay the expression of CxS43 at messenger ribonucleic acid (mRNA) and protein levels. As shown in [Figure 2] and 2c, CxS43 was up-regulated by MSC treatment at 10 μmol concentration both at mRNA and protein levels, with even higher level at 25 μmol MSC treatment. GAPDH and tubulin were used as loading controls for mRNA and protein assay.

Se-methylselenocysteine down-regulated B-cell lymphoma-2 and up-regulated bad expression

To explain the effects of MSC on cancer cell growth, we performed Western blot to show the alteration of protein Bcl-2 and bad, the two main players in the cancer cell apoptosis process. After the treatment of MSC at 25 μmol, Bcl-2 was down-regulated and bad was up-regulated. The Bcl-2 and bad levels, at 25 μmol MSC treatment were significantly different from that of control cells. By stably expressing CxS43 protein, Bcl-2 was also down-regulated, and bad was up-regulated, which was consistent with that in MSC-treated cells. These data indicate that MSC may regulate the expression of Bcl-2 and bad through CxS43 signaling pathway [Figure 3].
Figure 3: Se-methylselenocysteine (MSC) treatment down-regulates B-cell lymphoma-2 (Bcl-2) and up-regulates bad expression. (a and c) Cell treated with two different concentrations of MSC (10 μmol and 25 μmol), Bcl-2 and bad expression was assessed by Western blot analysis, tubulin as loaded control. (b and d) Western blot assay examines the Bcl-2 and bad in vehicle control and Cx43-overexpressing DU145 cells. The expression of protein levels were quantified with density of the bands normalized by the tubulin as control (Con = control; Cx43 = connexin 43)

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Silencing of connexin 43 expression attenuated Se-methylselenocysteine-induced apoptosis

To explore whether CxS43 contributed to MSC-induced apoptosis, we exogenously expressed and silenced CxS43 to see the effects on cell apoptosis. By exogenously overexpressing CxS43, MSC was able to induce more intense apoptosis in DU145 cells, while CxS43 silence by siRNA attenuated the apoptosis effect of MSC [Figure 4]a and b]. This result indicates CxS43 plays role in MSC-induced cancer cell apoptosis.
Figure 4: Effects of connexin 43 (Cx43) on Se-methylselenocysteine (MSC)-induced apoptosis in DU145 cells. (a) Overexpression of Cx43 enhanced the sensitivity of DU145 cells to MSC-induced apoptosis, while Cx43 silence by specific small interfering ribonucleic acid (siRNA) impaired MSC efficacy. (b) Western blot showed the change of pre-PARP levels between the samples. (Cx43 exp = Cx43 expression; Cx43 Si = Cx43 siRNA)

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 > Discussion Top

Selenium is an essential micronutrient for animals with several important biological functions. Recent studies have revealed the chemopreventive effects of selenocompounds. [16],[17],[18] The inhibitory effects of the selenocompounds on cell proliferation, with a preference for tumor cells versus nontransformed cells, were considered the most feasible mechanism. [19] It was supposed that the apoptosis-inducing ability of selenium is related to its chemopreventive activity. [20] It has been reported that selenium-containing compound of MSC had anticancer effects. Though Hurst et al. have found collagen expression was altered by MSC in PCa cells, [21] the mechanisms underlying the anticancer effects of selenocompounds remains unclear. Exploring the probable mechanism of selenocompound may provide novel strategies for cancer treatment.

Se-methylselenocysteine has been regarded as a powerful chemopreventive reagent owing to its activity against cancer and low toxicity. [7],[22] Our study demonstrates that MSC is a more efficient selenocompound to induce growth inhibition and apoptosis in DU145 PCa cells. DU145 is a widely used the model to test the anticancer activity of various compounds, notably in the studies exploring mechanisms of apoptosis. [23],[24]

First, we studied the biological function of MSC to inhibit cancer cell growth and proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assay. As shown in [Figure 1], MSC exerted growth-suppressing effects on DU145 cells. Correspondingly, the colony formation ability of DU145 was also impaired with MSC treatment, indicating its capacity in lowering the carcinogenicity of cancer cells.

Subsequently, we performed experiments to show that MSC induced significant cancer cell apoptosis in a dose-dependent manner. At 25 μmol of concentration, MSC produced apoptosis in about 40% of the cancer cells. Our results were supported by the previous report that MSC was effective to induce apoptosis in HL60 cancer cells. [20] In that study, MSC induced apoptosis through activation of caspase cascades. In our study, we explored that MSC re-established the balance between anti-and pro-apoptotic molecules, by inactivating the expression of Bcl-2 and activating the expression of bad, to facilitate apoptosis. Furthermore, we showed that MSC treatment activated the expression of CxS43, which is a structural protein of gap-junction for intercellular communication and has been shown to be required for the anti-apoptotic effects of bisphosphonates in osteocyte and osteoblast. [25] To confirm whether CxS43, in this experimental circumstance, was involved in MSC-induced cancer cell apoptosis, we over-expressed CxS43 to show its regulation on Bcl-2 and bad proteins. Results showed the consistent pattern of CxS43 to MSC on regulating these apoptosis-associated molecules.

As to the mechanisms of MSC to suppress cancer cell growth and induce cancer cell apoptosis, here we showed that MSC induced Bcl-2 down-regulation and bad up-regulation. Yeo et al. have reported that MSC induced apoptosis through caspase activation and cisplatin-mediated Bax cleavage in SKOV-3 ovary cancer cells. Caspase activation is the down-stream events of Bcl-2 family proteins rebalance in the process of apoptosis. That study and our data converged concerning the apoptosis pathway by MSC treatment. Lee et al. indicated that MSC sensitized TRAIL-mediated apoptosis via down-regulation of Bcl-2 expression. [5] Previous studies have shown that MSC sensitized hypoxic tumor cells to irinotecan by targeting hypoxia-inducible factor-1 alpha and hence its transcriptionally regulated genes vascular epithelial growth factor and carbonic anhydrase IX. [26] However, before our study, no data had focused on the network between MSC and apoptosis-associated proteins, such as Bcl-2 and bad. To show that MSC-induced apoptosis was going through CxS43, at least partially, we silenced the expression of CxS43 and detected the subsequent apoptosis by flow cytometry assay. CxS43 silencing significantly reversed the MSC-induced apoptosis in DU145 cancer cells. Collectively, these data supported that CxS43 contributed to MSC-mediated apoptosis in PCa cell DU145. This report is the first to show that CxS43, a player in gap junction-mediated intercellular communication is involved in MSC-induced apoptosis in PCa cells.

These findings guarantee further studies of MSC in a wide spectrum of cancer cells and its mechanisms in inducing apoptosis.

 > References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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