Simvastatin in combination with meclofenamic acid inhibits the proliferation and migration of human prostate cancer PC‑3 cells via an AKR1C3 mechanism

Sekine,Yoshitaka; Nakayama,Hiroshi; Miyazawa,Yoshiyuki; Kato,Haruo; Furuya,Yosuke; Arai,Seiji; Koike,Hidekazu; Matsui,Hiroshi; Shibata,Yasuhiro; Ito,Kazuto; Suzuki,Kazuhiro

doi:10.3892/ol.2017.7721

Simvastatin in combination with meclofenamic acid inhibits the proliferation and migration of human prostate cancer PC‑3 cells via an AKR1C3 mechanism

Authors:
- Yoshitaka Sekine
- Hiroshi Nakayama
- Yoshiyuki Miyazawa
- Haruo Kato
- Yosuke Furuya
- Seiji Arai
- Hidekazu Koike
- Hiroshi Matsui
- Yasuhiro Shibata
- Kazuto Ito
- Kazuhiro Suzuki
View Affiliations

Affiliations: Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371‑8511, Japan
Published online on: December 29, 2017 https://doi.org/10.3892/ol.2017.7721
Pages: 3167-3172

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Statins have become of interest in research due to their anticancer effects. However, the exact mechanism of their anticancer properties remains unclear. The authors previously reported that statins decrease intracellular cholesterol levels in androgen‑independent prostate cancer cells. In de novo androgen synthesis, cholesterol is the primary material and certain enzymes have important roles. The present study aimed to determine whether simvastatin alters the expression of androgen synthesis‑associated enzymes in androgen‑independent prostate cancer cells. A novel combination therapy of statins and other drugs that inhibit the overexpression of enzymes involved in androgen synthesis was explored. The cytotoxicity of simvastatin and meclofenamic acid was assessed in prostate cancer cells using MTS and migration assays. Testosterone and dihydrotestosterone concentrations in the culture medium were measured using liquid chromatography-tandem mass spectrometry. RAC‑α‑serine/threonine‑protein kinase (Akt) phosphorylation was detected by western blot analysis. Following treatment with simvastatin, aldo‑keto reductase family 1 member C3 (AKR1C3) expression increased in PC‑3 (>60‑fold) and LNCaP‑LA cells, however not in 22Rv1 cells. Small interfering (si)RNA was used to clarify the effects of AKR1C3 expression. The reduction in AKR1C3 expression in PC‑3 cells following siRNA transfection was not associated with basal cell proliferation and migration; however, treatment with simvastatin decreased cell proliferation and migration. The combination of simvastatin and meclofenamic acid, an AKR1C3 inhibitor, further enhanced the inhibition of cell proliferation and migration compared with treatment with either drug alone. Furthermore, treatment with simvastatin attenuated insulin‑like growth factor 1‑induced Akt activation; however, the combination of simvastatin and meclofenamic acid further inhibited Akt activation. These results suggest that the combination of simvastatin and meclofenamic acid may be an effective strategy for the treatment of castration‑resistant prostate cancer.

View Figures

View References

1	Zhong S, Zhang X, Chen L, Ma T, Tang J and Zhao J: Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev. 41:554–567. 2015. View Article : Google Scholar : PubMed/NCBI
2	Bansal D, Undela K, D'Cruz S and Schifano F: Statin use and risk of prostate cancer: A meta-analysis of observational studies. PLoS One. 7:e466912012. View Article : Google Scholar : PubMed/NCBI
3	Platz EA, Tangen CM, Goodman PJ, Till C, Parnes HL, Figg WD, Albanes D, Neuhouser ML, Klein EA, Lucia MS, et al: Statin drug use is not associated with prostate cancer risk in men who are regularly screened. J Urol. 192:379–384. 2014. View Article : Google Scholar : PubMed/NCBI
4	Sekine Y, Furuya Y, Nishii M, Koike H, Matsui H and Suzuki K: Simvastatin inhibits the proliferation of human prostate cancer PC-3 cells via down-regulation of the insulin-like growth factor 1 receptor. Biochem Biophys Res Commun. 372:356–361. 2008. View Article : Google Scholar : PubMed/NCBI
5	Miyazawa Y, Sekine Y, Kato H, Furuya Y, Koike H and Suzuki K: Simvastatin Up-regulates annexin A10 that can inhibit the proliferation, migration, and invasion in androgen-independent human prostate cancer cells. Prostate. 77:337–349. 2017. View Article : Google Scholar : PubMed/NCBI
6	Furuya Y, Sekine Y, Kato H, Miyazawa Y, Koike H and Suzuki K: Low-density lipoprotein receptors play an important role in the inhibition of prostate cancer cell proliferation by statins. Prostate Int. 4:56–60. 2016. View Article : Google Scholar : PubMed/NCBI
7	Sobel RE and Sadar MD: Cell lines used in prostate cancer research: A compendium of old and new lines-part 1. J Urol. 173:342–359. 2005. View Article : Google Scholar : PubMed/NCBI
8	Suzuki K, Koike H, Matsui H, Ono Y, Hasumi M, Nakazato H, Okugi H, Sekine Y, Oki K, Ito K, et al: Genistein, a soy isoflavone, induces glutathione peroxidase in the human prostate cancer cell lines LNCaP and PC-3. Int J Cancer. 99:846–852. 2002. View Article : Google Scholar : PubMed/NCBI
9	Dozmorov MG, Azzarello JT, Wren JD, Fung KM, Yang Q, Davis JS, Hurst RE, Culkin DJ, Penning TM and Lin HK: Elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell-mediated endothelial cell tube formation: Implications for prostate cancer progression. BMC Cancer. 10:6722010. View Article : Google Scholar : PubMed/NCBI
10	Flanagan JU, Yosaatmadja Y, Teague RM, Chai MZ, Turnbull AP and Squire CJ: Crystal structures of three classes of non-steroidal anti-inflammatory drugs in complex with aldo-keto reductase 1C3. PLoS One. 8:e439652012. View Article : Google Scholar
11	Zhuang L, Kim J, Adam RM, Solomon KR and Freeman MR: Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. J Clin Invest. 115:959–968. 2005. View Article : Google Scholar : PubMed/NCBI
12	Sivaprasad U, Abbas Tand and Dutta V: Differential efficacy of 3-hydroxy-3-methlyglutaryl CoA reductase inhibitors on the cell cycle of prostate cancer cells. Mol Cancer Ther. 5:2310–2316. 2006. View Article : Google Scholar : PubMed/NCBI
13	Cai C, Chen S, Ng P, Bubley GJ, Nelson PS, Mostaghel EA, Marck B, Matsumoto AM, Simon NI, Wang H, et al: Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 71:6503–6513. 2011. View Article : Google Scholar : PubMed/NCBI
14	Matsuura K, Shiraishi H, Hara A, Sato K, Deyashiki Y, Ninomiya M and Sakai S: Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D2 11-ketoreductase activity. J Biochem. 124:940–946. 1998. View Article : Google Scholar : PubMed/NCBI
15	Azzarello JT, Lin HK, Gherezghiher A, Zakharov V, Yu Z, Kropp BP, Culkin DJ, Penning TM and Fung KM: Expression of AKR1C3 in renal cell carcinoma, papillary urothelial carcinoma, and Wilms' tumor. Int J Clin Exp Pathol. 3:147–155. 2009.PubMed/NCBI
16	Byrns MC, Duan L, Lee SH, Blair IA and Penning TM: Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer. J Steroid Biochem Mol Biol. 118:177–187. 2010. View Article : Google Scholar : PubMed/NCBI
17	Nakamura Y, Suzuki T, Nakabayashi M, Endoh M, Sakamoto K, Mikami Y, Moriya T, Ito A, Takahashi S, Yamada S, et al: In situ androgen producing enzymes in human prostate cancer. Endocr Relat Cancer. 12:101–107. 2005. View Article : Google Scholar : PubMed/NCBI
18	Stanbrough M, Bubley G, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG and Balk SP: Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 66:2815–2825. 2006. View Article : Google Scholar : PubMed/NCBI
19	Wako K, Kawasaki T, Yamana K, Suzuki K, Jiang S, Umezu H, Nishiyama T, Takahashi K, Hamakubo T, Kodama T and Naito M: Expression of androgen receptor through androgen-converting enzymes is associated with biological aggressiveness in prostate cancer. J Clin Pathol. 61:448–454. 2008. View Article : Google Scholar : PubMed/NCBI
20	Byrns MC, Jin Y and Penning TM: Inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3): Overview and structural insights. J Steroid Biochem Mol Biol. 125:95–104. 2011. View Article : Google Scholar : PubMed/NCBI
21	Kalgutkar AS, Crews BC, Rowlinson SW, Marnett AB, Kozak KR, Remmel RP and Marnett LJ: Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. Proc Natl Acad Sci USA. 97:pp. 925–930. 2000; View Article : Google Scholar : PubMed/NCBI
22	Ouellet M and Percival MD: Effect of inhibitor time-dependency on selectivity towards cyclooxygenase isoforms. Biochem J. 306:247–251. 1995. View Article : Google Scholar : PubMed/NCBI
23	Soriano-Hernández AD, Galvan-Salazar HR, Montes-Galindo DA, Rodriguez-Hernandez A, Martinez-Martinez R, Guzman-Esquivel J, Valdez-Velazquez LL, Baltazar-Rodriguez LM, Espinoza-Gómez F, Rojas-Martinez A, et al: Antitumor effect of meclofenamic acid on human androgen-independent prostate cancer: A preclinical evaluation. Int Urol Nephrol. 44:471–477. 2012. View Article : Google Scholar : PubMed/NCBI
24	Zheng X, Cui XX, Avila GE, Huang MT, Liu Y, Patel J, Kong AN, Paulino R, Shih WJ, Lin Y, et al: Atorvastatin and celecoxib inhibit prostate PC-3 tumors in immunodeficient mice. Clin Cancer Res. 13:5480–5487. 2007. View Article : Google Scholar : PubMed/NCBI
25	Wang H, Cui XX, Goodin S, Ding N, Van Doren J, Du Z, Huang MT, Liu Y, Cheng X, Dipaola RS, et al: Inhibition of IL-6 expression in LNCaP prostate cancer cells by a combination of atorvastatin and celecoxib. Oncol Rep. 31:835–841. 2014. View Article : Google Scholar : PubMed/NCBI
26	Fraser M, Berlin A, Bristow RG and van der Kwast T: Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer. Urol Oncol. 33:85–94. 2015. View Article : Google Scholar : PubMed/NCBI