Simvastatin blocks TGF-β1-induced epithelial-mesenchymal transition in human prostate cancer cells

Xie,Feng; Liu,Jie; Li,Chengwen; Zhao,Yaorui

doi:10.3892/ol.2016.4404

Simvastatin blocks TGF-β1-induced epithelial-mesenchymal transition in human prostate cancer cells

Authors:
- Feng Xie
- Jie Liu
- Chengwen Li
- Yaorui Zhao
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Affiliations: Department of Urology, Affiliated Hospital of Logistics University of Chinese People's Armed Police Forces, Tianjin 300162, P.R. China, Department of Urology, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
Published online on: April 1, 2016 https://doi.org/10.3892/ol.2016.4404
Pages: 3377-3383

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Abstract

In recent years, the use of statins has been reported to be associated with a reduced risk of prostate cancer (PCa), particularly metastatic PCa. The mechanisms underlying these epidemiological observations are poorly understood. Epithelial-mesenchymal transition (EMT) is a critical initial step and a hallmark for cancer metastasis. In the present study, the relationship between simvastatin and EMT in PCa and the mechanism involved was investigated. It was demonstrated that simvastatin inhibited the EMT as assessed by reduced expression of N‑cadherin and vimentin, and increased E‑cadherin in TGF‑β1 treated DU145 PCa cells. Furthermore, simvastatin inhibited TGF‑β1‑induced migration and invasion of DU145 cells. The TGF‑β1/Smad pathway and non‑Smad pathway were investigated in simvastatin-treated DU145 cells. Simvastatin had no effect on TGF-β1-induced phosphorylation of Smad2 and Smad3. In the non-Smad pathway, simvastatin reduced TGF‑β1‑induced p38 MAPK phosphorylation, but had no effect on TGF‑β1‑induced Erk1/2 phosphorylation. Simvastatin attenuated TGF‑β1‑induced EMT, cell migration and invasion in DU145 cells. These effects may have been mediated by the inhibition of p38 MAPK phosphorylation, not through the canonical Smad pathway. Therefore simvastatin may be a promising therapeutic agent for treating PCa.

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1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
2	Platz EA, Leitzmann MF, Visvanathan K, Rimm EB, Stampfer MJ, Willett WC and Giovannucci E: Statin drugs and risk of advanced prostate cancer. J Natl Cancer Inst. 98:1819–1825. 2006. View Article : Google Scholar : PubMed/NCBI
3	Loeb S, Kan D, Helfand BT, Nadler RB and Catalona WJ: Is statin use associated with prostate cancer aggressiveness? BJU Int. 105:1222–1225. 2010. View Article : Google Scholar : PubMed/NCBI
4	Park YH, Seo SY, Lee E, Ku JH, Kim HH and Kwak C: Simvastatin induces apoptosis in castrate resistant prostate cancer cells by deregulating nuclear factor-κB pathway. J Urol. 189:1547–1552. 2013. View Article : Google Scholar : PubMed/NCBI
5	Yokomizo A, Shiota M, Kashiwagi E, Kuroiwa K, Tatsugami K, Inokuchi J, Takeuchi A and Naito S: Statins reduce the androgen sensitivity and cell proliferation by decreasing the androgen receptor protein in prostate cancer cells. Prostate. 71:298–304. 2011. View Article : Google Scholar : PubMed/NCBI
6	Brown M, Hart C, Tawadros T, et al: The differential effects of statins on the metastatic behaviour of prostate cancer. Br J Cancer. 106:1689–1696. 2012. View Article : Google Scholar : PubMed/NCBI
7	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
8	Zavadil J and Böttinger EP: TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 24:5764–5774. 2005. View Article : Google Scholar : PubMed/NCBI
9	Wikström P, Stattin P, Franck-Lissbrant I, Damber JE and Bergh A: Transforming growth factor beta1 is associated with angiogenesis, metastasis and poor clinical outcome in prostate cancer. Prostate. 37:19–29. 1998. View Article : Google Scholar : PubMed/NCBI
10	Javelaud D and Mauviel A: Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: Implications for carcinogenesis. Oncogene. 24:5742–5750. 2005. View Article : Google Scholar : PubMed/NCBI
11	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
12	Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F and Nieto MA: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2:76–83. 2000. View Article : Google Scholar : PubMed/NCBI
13	Bolós V, Peinado H, Pérez-Moreno MA, Fraga MF, Esteller M and Cano A: The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: A comparison with Snail and E47 repressors. J Cell Sci. 116:499–511. 2003. View Article : Google Scholar : PubMed/NCBI
14	Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, Berx G, Cano A, Beug H and Foisner R: DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene. 24:2375–2385. 2005. View Article : Google Scholar : PubMed/NCBI
15	Yang MH, Hsu DS, Wang HW, et al: Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol. 12:982–992. 2010. View Article : Google Scholar : PubMed/NCBI
16	Yang J and Weinberg RA: Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis. Dev Cell. 14:818–829. 2008. View Article : Google Scholar : PubMed/NCBI
17	González-Santiago AE, Mendoza-Topete LA, Sánchez-Llamas F, Troyo-Sanromán R and Gurrola-Díaz CM: TGF-β1 serum concentration as a complementary diagnostic biomarker of lung cancer: Establishment of a cut-point value. J Clin Lab Anal. 25:238–243. 2011. View Article : Google Scholar : PubMed/NCBI
18	Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D and van Roy F: The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell. 7:1267–1278. 2001. View Article : Google Scholar : PubMed/NCBI
19	Peinado H, Quintanilla M and Cano A: Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: Mechanisms for epithelial mesenchymal transitions. J Biol Chem. 278:21113–21123. 2003. View Article : Google Scholar : PubMed/NCBI
20	Janda E, Lehmann K, Killisch I, et al: Ras and TGF [beta] cooperatively regulate epithelial cell plasticity and metastasis: Dissection of Ras signaling pathways. J Cell Biol. 156:299–313. 2002. View Article : Google Scholar : PubMed/NCBI
21	Oft M, Heider KH and Beug H: TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol. 8:1243–1252. 1998. View Article : Google Scholar : PubMed/NCBI
22	Yang T, Chen M and Sun T: Simvastatin attenuates TGF-β1-induced epithelial-mesenchymal transition in human alveolar epithelial cells. Cell Physiol Biochem. 31:863–874. 2013. View Article : Google Scholar : PubMed/NCBI
23	Patel S, Mason RM, Suzuki J, et al: Inhibitory effect of statins on renal epithelial-to-mesenchymal transition. Am J Nephrol. 26:381–387. 2006. View Article : Google Scholar : PubMed/NCBI
24	Agrotis A: Simvastatin, an inhibitor of epithelial-to-mesenchymal transition in experimental atherosclerotic renovascular disease? J Hypertens. 26:1553–1555. 2008. View Article : Google Scholar : PubMed/NCBI
25	Urakami C, Kurosaka D, Tamada K, et al: Lovastatin alters TGF-β-induced epithelial-mesenchymal transition in porcine lens epithelial cells. Curr Eye Res. 37:479–485. 2012. View Article : Google Scholar : PubMed/NCBI
26	Ao M, Williams K, Bhowmick NA and Hayward SW: Transforming growth factor-beta promotes invasion in tumorigenic but not in nontumorigenic human prostatic epithelial cells. Cancer Res. 66:8007–8016. 2006. View Article : Google Scholar : PubMed/NCBI
27	Hotz B, Arndt M, Dullat S, Bhargava S, Buhr HJ and Hotz HG: Epithelial to mesenchymal transition: Expression of the regulators snail, slug and twist in pancreatic cancer. Clin Cancer Res. 13:4769–4776. 2007. View Article : Google Scholar : PubMed/NCBI
28	Moustakas A and Heldin CH: Non-Smad TGF-beta signals. J Cell Sci. 118:3573–3584. 2005. View Article : Google Scholar : PubMed/NCBI
29	Shi Y and Massagué J: Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 113:685–700. 2003. View Article : Google Scholar : PubMed/NCBI
30	Burke JP, Watson RW, Murphy M, Docherty NG, Coffey JC and O'Connell PR: Simvastatin impairs smad-3 phosphorylation and modulates transforming growth factor beta1-mediated activation of intestinal fibroblasts. Br J Surg. 96:541–551. 2009. View Article : Google Scholar : PubMed/NCBI
31	Park IH, Park SJ, Cho JS, Moon YM, Moon JH, Kim TH, Lee SH and Lee HM: Effect of simvastatin on transforming growth factor beta-1-induced myofibroblast differentiation and collagen production in nasal polyp-derived fibroblasts. Am J Rhinol Allergy. 26:7–11. 2012. View Article : Google Scholar : PubMed/NCBI
32	Yu L, Hébert MC and Zhang YE: TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J. 21:3749–3759. 2002. View Article : Google Scholar : PubMed/NCBI
33	Meyer-Ter-Vehn T, Katzenberger B, Han H, Grehn F and Schlunck G: Lovastatin inhibits TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts. Invest Ophthalmol Vis Sci. 49:3955–3960. 2008. View Article : Google Scholar : PubMed/NCBI
34	Jacobs EJ, Rodriguez C, Bain EB, Wang Y, Thun MJ and Calle EE: Cholesterol-lowering drugs and advanced prostate cancer incidence in a large US cohort. Cancer Epidemiol Biomarkers Prev. 16:2213–2217. 2007. View Article : Google Scholar : PubMed/NCBI
35	Murtola TJ, Tammela TL, Lahtela J and Auvinen A: Cholesterol-lowering drugs and prostate cancer risk: A population-based case-control study. Cancer Epidemiol Biomarkers Prev. 16:2226–2232. 2007. View Article : Google Scholar : PubMed/NCBI