Atorvastatin partially inhibits the epithelial-mesenchymal transition in A549 cells induced by TGF-β1 by attenuating the upregulation of SphK1

Fan,Zhiqiang; Jiang,Handong; Wang,Zili; Qu,Jieming

doi:10.3892/or.2016.4897

Atorvastatin partially inhibits the epithelial-mesenchymal transition in A549 cells induced by TGF-β1 by attenuating the upregulation of SphK1

Authors:
- Zhiqiang Fan
- Handong Jiang
- Zili Wang
- Jieming Qu
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Affiliations: Department of Pulmonary Medicine, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, P.R. China, Department of Pulmonary Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P.R. China, Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, P.R. China, Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China
Published online on: June 22, 2016 https://doi.org/10.3892/or.2016.4897
Pages: 1016-1022

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Abstract

Statins are the most effective drugs used in the reduction of intracellular synthesis of cholesterol. Numerous studies have confirmed that statins reduce the risk of multiple types of cancers. Statin use in cancer patients is associated with reduced cancer-related mortality. Epithelial-to-mesenchymal transition (EMT), a complicated process programmed by multiple genes, is an important mechanism of cancer metastasis. We explored the effect and mechanism of atorvastatin on the EMT process in A549 cells by establishing an EMT model in vitro induced by TGF-β1, and evaluated the effects of atorvastatin on the lower signaling pathway of TGF-β1 stimulation. Our results showed that atorvastatin partially inhibited the EMT process, and inhibited cell migration and actin filament remodeling. Transcriptional upregulation of ZEB1 and protein sphingosine kinase 1 (SphK1) induced by TGF-β1 was also suppressed. SphK1 plasmid transient transfection strengthened the EMT process induced by TGF-β1 in the presence of atorvastatin. Our experiments confirmed that atorvastatin can partially inhibit the EMT process of non-small cell lung cancer cells induced by TGF-β1 by attenuating the upregulation of SphK1.

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1	Herbst RS, Heymach JV and Lippman SM: Lung cancer. N Engl J Med. 359:1367–1380. 2008. View Article : Google Scholar : PubMed/NCBI
2	Mehlen P and Puisieux A: Metastasis: A question of life or death. Nat Rev Cancer. 6:449–458. 2006. View Article : Google Scholar : PubMed/NCBI
3	Tiwari N, Gheldof A, Tatari M and Christofori G: EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol. 22:194–207. 2012. View Article : Google Scholar : PubMed/NCBI
4	De Craene B and Berx G: Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 13:97–110. 2013. View Article : Google Scholar : PubMed/NCBI
5	Thiery JP, Acloque H, Huang RYJ and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
6	Liao JK: Clinical implications for statin pleiotropy. Curr Opin Lipidol. 16:624–629. 2005. View Article : Google Scholar : PubMed/NCBI
7	Gazzerro P, Proto MC, Gangemi G, Malfitano AM, Ciaglia E, Pisanti S, Santoro A, Laezza C and Bifulco M: Pharmacological actions of statins: A critical appraisal in the management of cancer. Pharmacol Rev. 64:102–146. 2012. View Article : Google Scholar
8	Demierre MF, Higgins PD, Gruber SB, Hawk E and Lippman SM: Statins and cancer prevention. Nat Rev Cancer. 5:930–942. 2005. View Article : Google Scholar : PubMed/NCBI
9	Menter DG, Ramsauer VP, Harirforoosh S, Chakraborty K, Yang P, Hsi L, Newman RA and Krishnan K: Differential effects of pravastatin and simvastatin on the growth of tumor cells from different organ sites. PLoS One. 6:e288132011. View Article : Google Scholar
10	Rao S, Porter DC, Chen X, Herliczek T, Lowe M and Keyomarsi K: Lovastatin-mediated G₁ arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci USA. 96:7797–7802. 1999. View Article : Google Scholar
11	Liu Y, Tang W, Wang J, Xie L, Li T, He Y, Deng Y, Peng Q, Li S and Qin X: Association between statin use and colorectal cancer risk: A meta-analysis of 42 studies. Cancer Causes Control. 25:237–249. 2014. View Article : Google Scholar
12	Khurana V, Bejjanki HR, Caldito G and Owens MW: Statins reduce the risk of lung cancer in humans: A large case-control study of US veterans. Chest. 131:1282–1288. 2007. View Article : Google Scholar : PubMed/NCBI
13	Shi M, Zheng H, Nie B, Gong W and Cui X: Statin use and risk of liver cancer: An update meta-analysis. BMJ Open. 4:e0053992014. View Article : Google Scholar : PubMed/NCBI
14	Lustman A, Nakar S, Cohen AD and Vinker S: Statin use and incident prostate cancer risk: Does the statin brand matter? A population-based cohort study. Prostate Cancer Prostatic Dis. 17:6–9. 2014. View Article : Google Scholar
15	Nielsen SF, Nordestgaard BG and Bojesen SE: Statin use and reduced cancer-related mortality. N Engl J Med. 367:1792–1802. 2012. View Article : Google Scholar : PubMed/NCBI
16	Baker DL, Pham TC and Sparks MA: Structure and catalytic function of sphingosine kinases: Analysis by site-directed mutagenesis and enzyme kinetics. Biochim Biophys Acta. 1831:139–146. 2013. View Article : Google Scholar
17	Kono Y, Nishiuma T, Nishimura Y, Kotani Y, Okada T, Nakamura S and Yokoyama M: Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1. Am J Respir Cell Mol Biol. 37:395–404. 2007. View Article : Google Scholar : PubMed/NCBI
18	Milara J, Navarro R, Juan G, Peiró T, Serrano A, Ramón M, Morcillo E and Cortijo J: Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition. Thorax. 67:147–156. 2012. View Article : Google Scholar
19	Ai J, Tang Q, Wu Y, Xu Y, Feng T, Zhou R, Chen Y, Gao X, Zhu Q, Yue X, et al: The role of polymeric immunoglobulin receptor in inflammation-induced tumor metastasis of human hepatocellular carcinoma. J Natl Cancer Inst. 103:1696–1712. 2011. View Article : Google Scholar : PubMed/NCBI
20	Haynes J, Srivastava J, Madson N, Wittmann T and Barber DL: Dynamic actin remodeling during epithelial-mesenchymal transition depends on increased moesin expression. Mol Biol Cell. 22:4750–4764. 2011. View Article : Google Scholar : PubMed/NCBI
21	Wendt MK, Allington TM and Schiemann WP: Mechanisms of the epithelial-mesenchymal transition by TGF-beta. Future Oncol. 5:1145–1168. 2009. View Article : Google Scholar : PubMed/NCBI
22	Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, et al: Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 339:580–584. 2013. View Article : Google Scholar : PubMed/NCBI
23	Miraglia E, Högberg J and Stenius U: Statins exhibit anticancer effects through modifications of the pAkt signaling pathway. Int J Oncol. 40:867–875. 2012.
24	Argast GM, Krueger JS, Thomson S, Sujka-Kwok I, Carey K, Silva S, O'Connor M, Mercado P, Mulford IJ, Young GD, et al: Inducible expression of TGFβ, Snail and Zeb1 recapitulates EMT in vitro and in vivo in a NSCLC model. Clin Exp Metastasis. 28:593–614. 2011. View Article : Google Scholar : PubMed/NCBI
25	Alves CC, Carneiro F, Hoefler H and Becker KF: Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers. Front Biosci. 14:3035–3050. 2009. View Article : Google Scholar
26	Shida D, Takabe K, Kapitonov D, Milstien S and Spiegel S: Targeting SphK1 as a new strategy against cancer. Curr Drug Targets. 9:662–673. 2008. View Article : Google Scholar : PubMed/NCBI
27	Xin C, Ren S, Kleuser B, Shabahang S, Eberhardt W, Radeke H, Schäfer-Korting M, Pfeilschifter J and Huwiler A: Sphingosine 1-phosphate cross-activates the Smad signaling cascade and mimics transforming growth factor-beta-induced cell responses. J Biol Chem. 279:35255–35262. 2004. View Article : Google Scholar : PubMed/NCBI