Research ArticleExperimental Studies

Simvastatin Enhances the Radiosensitivity of Androgen-independent Prostate Cancer Cells via Inhibition of RAD51 Expression

DAISUKE OKA, YOSHITAKA SEKINE, YUSUKE TSUJI, HIROSHI NAKAYAMA, YOSHIYUKI MIYAZAWA, SEIJI ARAI, HIDEKAZU KOIKE and KAZUHIRO SUZUKI
Anticancer Research January 2024, 44 (1) 93-98; DOI: https://doi.org/10.21873/anticanres.16791

Abstract

Background/Aim: Statins exert antitumor effects via various mechanisms. Additionally, the recurrence rate of prostate cancer after radiation therapy is lower in patients taking statins. This study investigated the efficacy of combination therapy with statins and irradiation in androgen-independent prostate cancer cells. Materials and Methods: PC-3 and LNCaP human prostate cancer cell lines were used in this study. We developed androgen-independent LNCaP cells (LNCaP-LA) by gradually replacing fetal bovine serum (FBS) with charcoal-stripped FBS. Microarray analysis was performed, followed by Ingenuity Pathway Analysis. Cell viability was determined using the MTS assay. Results: Simvastatin alters gene expressions in PC-3 cells. Microarray data showed that the number of differentially expressed genes was the highest in the pathway of “Role of BRCA1 in DNA Damage Response”. In the validation, the expression of RAD51, listed in “Role of BRCA1 in DNA Damage Response”, decreased significantly by simvastatin in PC-3 cells. Reduction in RAD51 expression following siRNA transfection increased the cytocidal effects of X-ray therapy in PC-3 and LNCaP-LA cells. The combination of simvastatin and irradiation further inhibited cell proliferation compared with monotherapy with either therapy in PC-3 or LNCaP-LA cells. In addition, compared with X-ray monotherapy, the combination of simvastatin and irradiation further enhanced the expression of γH2AX, which is reported to be one of the accurate markers of DNA damage in PC-3 cells. Conclusion: Simvastatin decreased the expression of RAD51 in androgen-independent prostate cancer cells. The combination of irradiation and drugs that reduce RAD51 expression can potentially affect androgen-independent prostate cancer growth.

Key Words:

Prostate cancer is one of the most common types of cancer in men (1). Radiation therapy (RT) is the treatment of choice for localized prostate cancer, but recurrence may occur after radiation therapy; therefore, radiation therapy effectiveness needs to be improved.

Statins are used to prevent cardiovascular disease. Some reports have shown that statins exert antitumor effects on prostate cancer. So far, it has been shown that they not only lower intracellular cholesterol in prostate cancer cells (2), but also have antitumor effects through various mechanisms against prostate cancer (3-6).

Regarding the effects of statin combination therapy on prostate cancer radiotherapy, there have been reports that statins have improved clinical effects in prostate cancer patients treated with radiation therapy (7, 8) but the mechanisms are unclear.

In a previous study (5), we investigated the effect of statins on gene expression in androgen-independent prostate cancer PC-3 cells, which are reported as radiation-resistant cells (9). Using microarray data, pathway analysis revealed that simvastatin downregulated DNA repair genes. DNA repair genes play essential roles in DNA repair following DNA damage caused by irradiation (10). In this study, we investigated the efficacy of combination therapy using statins and irradiation for androgen-independent prostate cancer cells.

Materials and Methods

Cells and chemicals. Human prostate cancer cell lines, PC-3 and LNCaP, were purchased from DS Pharma Biomedical (Osaka, Japan) and cultured in RPMI 1640 (Sigma-Aldrich, St. Louis, MO, USA) supplemented with 10% fetal bovine serum (FBS) (Moregate, Bulimba, Australia). LNCaP-LA cells, generated from LNCaP cells, were cultured in a medium containing 10% charcoal-stripped FBS (CS-FBS) for >3 months. Rabbit anti-RAD51 monoclonal antibody, rabbit anti-γH2AX monoclonal antibody, and rabbit anti-human β-actin monoclonal antibody were purchased from Cell Signaling (Beverly, MA, USA), Cell Signaling, and A&G Pharmaceutical (Columbia, MD, USA), respectively.

Pathway analysis of microarray data. Our previous study performed microarray analysis on PC-3 cells after simvastatin treatment (5). Briefly, Human Gene Expression ver. A 2 4×44 K Microarray Kit (Agilent Technologies, Santa Clara, CA, USA) was used according to the protocol of the manufacturer (Hokkaido Systems Science Co., Ltd., Sapporo, Japan). Probes showing significantly different expression levels were extracted using the filtering criteria of an 8.0-fold change and p<0.001 using GeneSpring GX (ver. 7.3) (Agilent Technologies) after per-chip and per-gene normalization. Differences in values were evaluated using an unpaired t-test. The differentially expressed genes (DEGs) of the signaling pathways were assessed using the Ingenuity® iReport™ online software (Ingenuity® Systems). Genes with a change in expression of at least 1.5-fold from the controls and p-values <0.05 were included in the iReport analysis.

Quantification of mRNA levels. The mRNA levels were quantified using Applied Biosystems 7300 Real-Time PCR System (Applied Biosystems, Foster City, CA, USA). Complementary DNA (cDNA) synthesis was performed (11), and PCR amplification was carried out using 2 μl of cDNA and RAD51 primer (Hs00947967_m1, Applied Biosystems). Afterward, PCR was performed for one 10 min-cycle at 95°C, followed by 40 15 s-cycles at 95°C and 60 s at 60°C. β-Actin (Applied Biosystems) transcript levels were used as an internal control. The mRNA fold changes were determined using the comparative CT (2−ΔΔCt) cycle (ΔCt) method (12).

Western blotting assays. Cell lysates were prepared in radioimmunoprecipitation assay (RIPA) buffer (Applied Biosystems) containing protease inhibitors (complete without ethylenediaminetetraacetic acid, Roche Diagnostics, Basel, Switzerland). Equal amounts of proteins (20-40 μg/lane) were electrophoresed on 4%-12% sodium dodecyl sulfate-polyacrylamide gel and transferred onto nitrocellulose membranes. Each membrane was incubated with one of the antibodies as above: RAD51 (1:1,000), γH2AX (1:1,000), and β-actin (1:1,000) at 4°C overnight. The blots were developed using a 1:2,000 dilution of horseradish peroxidase (HRP)-conjugated secondary antibody (Cell Signaling). Proteins were visualized using the Immobilon Western HRP Reagent (Millipore, Burlington, MA, USA). Representative images of three independent experiments are shown in each figure.

siRNA transfection experiments. Cells were transfected with ON-TARGETplus Non-targeting Pool (No. D-001810-10-05; Dharmacon, Waltham, MA, USA) or ON-TARGETplus Human RAD51 siRNA (No. L-003530-00-0005; Dharmacon) using DharmaFect (Dharmacon). Cells were incubated for 48 h after transfection.

Cell proliferation assay. Cells were plated onto a 96-well plate in a 100-μl culture medium. After 24 h, cells were incubated with a medium containing simvastatin (PC-3, 2 μM; LNCaP-LA, 5 μM). Irradiation was administered 48 h later (PC-3 cells, 4 Gy; LNCaP-LA cells, 2 Gy). After incubation, the number of living cells was measured using the MTS assay. The optical density of the cell lysate was expressed as fold change.

Cell irradiation. X-ray irradiation was performed using the MultiRad 225 X-ray irradiation system (Faxitron, Wheeling, IL, USA).

Statistical analysis. Unless otherwise indicated, all data are expressed as the mean±standard deviation. Differences between values were evaluated using either an unpaired t-test for two groups or a one-way analysis of variance with Tukey’s post hoc analysis for more than three groups. Statistical significance was set at p<0.05.

Results

Pathway analysis after treatment of PC-3 cells with simvastatin. DEGs were the highly enriched in the pathway of “Role of BRCA1 in DNA Damage Response” (Table I). The DEGs in this pathway are known to be DNA repair genes (13). The names of DEGs in the “Role of BRCA1 in DNA Damage Response” pathway are highlighted in blue fonts in Figure 1. Among these genes, listed as “Role of BRCA1 in DNA Damage Response” pathway, we focused on RAD51, which has been correlated with radiosensitivity and progression of aggressive prostate cancer (14, 15).

View this table:
Table I.

Number of differentially expressed genes in each pathway in PC-3 cells after treatment with simvastatin compared to the control.

Figure 1.
Figure 1.

Schematic of the “Role of BRCA1 in DNA Damage Response” pathway associated with differentially expressed genes (DEGs). The proteins encoded by the DEGs involved in the signaling pathway are highlighted in colored font; the down-regulated DEGs are shown in blue.

The expression of RAD51 in androgen-independent prostate cancer cells after treatment with simvastatin. A quantitative reverse transcription-polymerase chain reaction was performed for validation. Simvastatin decreased the mRNA expression of RAD51 in PC-3 and LNCaP-LA cells (Figure 2A). The protein levels of RAD51 were evaluated using western blotting. Simvastatin also reduced the protein levels of RAD51 in PC-3 and LNCaP-LA cells (Figure 2B).

Figure 2.
Figure 2.

Effects of simvastatin on the expression of RAD51 in PC-3 and LNCaP-LA cells. The cells were incubated in a medium containing various concentrations of simvastatin. After 48 h, total RNA (A) and protein (B) levels were determined. A) mRNA expression of RAD51 was evaluated in real-time polymerase chain reaction tests, and the relative quantitative expression was calculated by comparing with the expression of b-actin. Values are expressed as mean±standard deviation (SD) (n=4). **p<0.01 vs. 0 μM, *p<0.05 vs. 0 μM. B) Protein expression of RAD51 was evaluated using western blotting. A representative experiment is shown, which was repeated thrice with similar results.

The effect of RAD51 inhibition on irradiation-induced inhibition of cell proliferation in androgen-independent prostate cancer cells. To assess whether decreased RAD51 expression affects the irradiation-induced impairment of cell proliferation, we knocked down RAD51 expression by transfection with small siRNAs. After siRNA transfection, RAD51 mRNA expression was reduced in PC-3 and LNCaP-LA cells (Figure 3A). The suppression of RAD51 expression by siRNA transfection enhanced the cytostatic effects of irradiation in both PC-3 and LNCaP-LA cells (Figure 3B).

Figure 3.
Figure 3.

Effects of RAD51 siRNA on PC-3 and LNCaP-LA cells. A. Effect of siRNA on RAD51 expression in PC-3 and LNCaP-LA cells. Cells transfected with RAD51 siRNA or negative control siRNA were incubated for 48 h before harvesting for real-time polymerase chain reaction. Values are expressed as mean±standard deviation (SD) (n=4). *p<0.01 vs. negative. B. Irradiation was administered (PC-3; 4 Gy, LNCaP-LA; cells, 2 Gy) 48 h after siRNA transfection. After 48 h for PC-3 cells and 72 h for LNCaP-LA cells, the number of viable cells was evaluated using MTS assay. Values are expressed as mean±SD (n=5). *p<0.05. N: negative; R: RAD51; Ra: radiation.

The combination effects of simvastatin and irradiation on cell proliferation in androgen-independent prostate cancer cells. We evaluated the effect of combining simvastatin and irradiation on the proliferation of PC-3 and LNCaP-LA cells. Treatment with simvastatin or irradiation alone inhibited cell proliferation, whereas combining the two treatments further enhanced the inhibition of cell proliferation in both cell lines (Figure 4).

Figure 4.
Figure 4.

Effects of simvastatin and irradiation combination therapy on PC-3 and LNCaP-LA cells. The cells were cultured in the medium with or without simvastatin (PC-3, 2 μM; LNCaP-LA, 5 μM). Irradiation was administered 48 h later (PC-3; 4 Gy, LNCaP-LA; cells, 2 Gy). After 48 h for PC-3 cells and 72 h for LNCaP-LA cells, the number of viable cells was evaluated using MTS assay. Values are expressed as the mean±standard deviation (SD) (PC-3, n=4; LNCaP-LA, n=5). **p<0.05, *p<0.05.

The effects of combination therapy of simvastatin and irradiation on γH2AX expression in PC-3 cells. γH2AX is reported to be a protein biomarker associated with DNA damage response (16). In PC-3 cells, γH2AX expression increased 1 h after irradiation and decreased after 6 h. However, in the group treated with simvastatin, the expression remained elevated even after 6 h (Figure 5).

Figure 5.
Figure 5.

Effects of the combination of simvastatin and irradiation on γH2AX expression in PC-3 cells. The cells were cultured with or without simvastatin (2 μM). Irradiation was administered 6 h later (4 Gy). After 6 h, the proteins were collected. Protein expression of γH2AX was evaluated using western blotting. A representative experiment is shown, which was repeated thrice with similar results.

Discussion

The main study findings were as follows: simvastatin decreased the expression of RAD51 in androgen-independent prostate cancer cells, and compared with either treatment alone, the combination of simvastatin and irradiation further enhanced the inhibition of androgen-independent prostate cancer cell proliferation. These results suggested that combining irradiation and drugs that decrease RAD51 expression could affect androgen-independent prostate cancer growth.

Radiotherapy is the primary treatment for prostate cancer. However, prostate cancer recurrence after radiotherapy is a major clinical problem. If the effects of radiotherapy can be improved, recurrence may be reduced. Various agents can sensitize prostate cancer (17). Nanoparticle-based radio-sensitizers improve visualization and discrimination by MRI (18). Enzalutamide has also been reported to enhance radiosensitization in human prostate cancer, mediated by decreased DNA repair (19). Studies have reported that statins increase radiosensitivity in various cancers, including prostate cancer (20, 21). In addition, statins may benefit patients with prostate cancer treated with RT clinically (7, 8). A meta-analysis showed that statin therapy improved the biochemical recurrence-free survival rate of patients who received radiotherapy for localized prostate cancer (22). Therefore, statins may have a radiosensitizing effect on prostate cancer treated with RT.

RAD51 plays a central role in DNA replication and homologous recombination repair (23). In previous studies, RAD51 was reported to be upregulated in some cancers and correlated with tumor metabolism, metastasis, and drug resistance (24). In addition, inhibition of RAD51 enhanced radiosensitivity in an in vitro model (25, 26). RAD51 is strongly expressed in high-grade prostate cancer (15), and inhibition of RAD51 expression enhances radiosensitivity in androgen-dependent prostate cancer LNCaP cells (14). In this study, the inhibition of RAD51 expression also enhanced radiosensitivity in androgen-independent prostate cancer PC-3 and LNCaP-LA cells. These results suggested that RAD51 inhibition can be combined with radiotherapy to enhance the efficacy of prostate cancer treatment.

Statins have various antitumor and anti-hyperlipidemic effects. Few studies have reported the effects of statins on RAD51 expression. In the skeletal muscle tissues of patients with statin myalgia undergoing a statin re-challenge, the expression of RAD51 was downregulated compared to that in statin-tolerant controls (27). Simvastatin decreases RAD51 protein levels in colon cancer cells (28). However, further studies are required to understand how statins affect RAD51 expression.

This study has several limitations. First, simvastatin concentrations used in the experiments were significantly higher than those used clinically (29). Second, the evaluations were only conducted at the cellular level, and in vivo experiments were not performed. Therefore, further investigation is necessary.

Conclusion

Simvastatin decreased the expression of RAD51 in androgen-independent prostate cancer cells. The combination of irradiation and drugs that reduce RAD51 expression can potentially affect androgen-independent prostate cancer growth.

Acknowledgements

The Authors thank Ms. Atusko Oyama and Ms. Hayumi Oayama for their technical assistance.

Footnotes

  • Authors’ Contributions

    Conception and design: DO and YS. Acquisition, analysis, and interpretation of data: DO, YS, YT, HN, and YM. Writing, review, and revision of the article: DO, YS, SA, HK, and KS.

  • Conflicts of Interest

    There are no financial or non-financial conflicts of interest to declare in relation to this study.

  • Funding

    This study was supported by JSPS KAKENHI (grant number: JP16K10995).

  • Received October 26, 2023.
  • Revision received December 6, 2023.
  • Accepted December 7, 2023.

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Simvastatin Enhances the Radiosensitivity of Androgen-independent Prostate Cancer Cells via Inhibition of RAD51 Expression
DAISUKE OKA, YOSHITAKA SEKINE, YUSUKE TSUJI, HIROSHI NAKAYAMA, YOSHIYUKI MIYAZAWA, SEIJI ARAI, HIDEKAZU KOIKE, KAZUHIRO SUZUKI
Anticancer Research Jan 2024, 44 (1) 93-98; DOI: 10.21873/anticanres.16791
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