Synergistic effect of receptor-interacting protein 140 and simvastatin on the inhibition of proliferation and survival of hepatocellular carcinoma cells

Xia,Kun; Zhang,Panpan; Hu,Jian; Hou,Huan; Xiong,Mingdi; Xiong,Junping; Yan,Nianlong

doi:10.3892/ol.2018.7831

Synergistic effect of receptor-interacting protein 140 and simvastatin on the inhibition of proliferation and survival of hepatocellular carcinoma cells

Authors:
- Kun Xia
- Panpan Zhang
- Jian Hu
- Huan Hou
- Mingdi Xiong
- Junping Xiong
- Nianlong Yan
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Affiliations: Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Basic Medical Experiments Center, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: January 19, 2018 https://doi.org/10.3892/ol.2018.7831
Pages: 4344-4350
Copyright: © Xia et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatocellular carcinoma is the sixth most prevalent malignant tumor and the third most common cause of cancer-associated mortality. Statins have been investigated for carcinoma prevention and treatment. In addition, receptor‑interacting protein 140 (RIP140) has been observed to inhibit the Wnt/β‑catenin signaling pathway and cell growth. The present study aimed to investigate whether simvastatin (SV) is able to induce SMCC‑7721 cell apoptosis through the Wnt/β‑catenin signaling pathway. Initially, a cell model of RIP140 overexpression was established, and then cells were treated with SV. The cell growth, viability and apoptosis were measured by cell counting kit‑8 and flow cytometry. Furthermore, the expression levels of RIP140, β‑catenin, c‑myc and cyclin D1 were detected by reverse transcription‑quantitative polymerase chain, western blot analysis and immunofluorescence. The results demonstrated that SV significantly increased the expression of RIP140 in SMCC‑7721 cells; however, β‑catenin, c‑myc and cyclin D1 levels were significantly decreased. Furthermore, the immunofluorescence assay of β‑catenin confirmed that SV decreased the content of this protein in SMCC‑7721 cells. Notably, RIP140 exerted a synergistic effect on the apoptosis rate induced by SV (RIP140 + SV group), while the alteration in RIP140, β‑catenin, c‑myc and cyclin D1 levels was more evident in the combination group as compared with the RIP140 or SV alone groups. In conclusion, these results suggested that SV is able to induce the apoptosis of SMCC‑7721 cells through the Wnt/β‑catenin signaling pathway, as well as that RIP140 and SV exert a synergistic effect on the inhibition of cell proliferation and survival.

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1	Istvan ES and Deisenhofer J: Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 292:1160–1164. 2001. View Article : Google Scholar : PubMed/NCBI
2	Lee Y, Lee KH, Lee GK, Lee SH, Lim KY, Joo J, Go YJ, Lee JS and Han JY: Randomized phase II study of afatinib plus simvastatin versus afatinib alone in previously treated patients with advanced nonadenocarcinomatous non-small cell lung cancer. Cancer Res Treat. 49:1001–1011. 2017. View Article : Google Scholar : PubMed/NCBI
3	Zhou YY, Zhu GQ, Wang Y, Zheng JN, Ruan LY, Cheng Z, Hu B, Fu SW and Zheng MH: Systematic review with network meta-analysis: Statins and risk of hepatocellular carcinoma. Oncotarget. 7:21753–21762. 2016.PubMed/NCBI
4	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
5	Blanc-Brude OP, Mesri M, Wall NR, Plescia J, Dohi T and Altieri DC: Therapeutic targeting of the survivin pathway in cancer: Initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis. Clin Cancer Res. 9:2683–2692. 2003.PubMed/NCBI
6	Li G, Zheng J, Xu B, Ling J, Qiu W and Wang Y: Simvastatin inhibits tumor angiogenesis in HER2-overexpressing human colorectal cancer. Biomed Pharmacother. 85:418–424. 2017. View Article : Google Scholar : PubMed/NCBI
7	Zhang Z, Zhang Y, Wang W, Hua Y, Liu L, Shen S and Peng B: Thrombocytopenia and the outcomes of hepatectomy for hepatocellular carcinoma: A meta-analysis. J Surg Res. 210:99–107. 2017. View Article : Google Scholar : PubMed/NCBI
8	Ferreira-Silva GÁ, Lages CC, Sartorelli P, Hasegawa FR, Soares MG and Ionta M: Casearin D inhibits ERK phosphorylation and induces downregulation of cyclin D1 in HepG2 cells. Toxicol In Vitro. 38:27–32. 2017. View Article : Google Scholar : PubMed/NCBI
9	Liu WH, Lee YM, Lam KK, Chen YF, Wang JJ, Yen MH and Cheng PY: The role of receptor-interacting protein 140 in the accumulation of fat in ovariectomised rats. Obes Surg. 21:935–940. 2011. View Article : Google Scholar : PubMed/NCBI
10	Mejhert N, Laurencikiene J, Pettersson AT, Kaaman M, Stenson BM, Rydén M and Dahlman I: Role of receptor-interacting protein 140 in human fat cells. BMC Endocr Disord. 10:12010. View Article : Google Scholar : PubMed/NCBI
11	Catalán V, Gómez-Ambrosi J, Lizanzu A, Rodríguez A, Silva C, Rotellar F, Gil MJ, Cienfuegos JA, Salvador J and Frühbeck G: RIP140 gene and protein expression levels are downregulated in visceral adipose tissue in human morbid obesity. Obes Surg. 19:771–776. 2009. View Article : Google Scholar : PubMed/NCBI
12	Lapierre M, Docquier A, Castet-Nicolas A, Gitenay D, Jalaguier S, Teyssier C and Cavaillès V: The emerging role of the transcriptional coregulator RIP140 in solid tumors. Biochim Biophys Acta. 1856:144–150. 2015.PubMed/NCBI
13	Aziz MH, Chen X, Zhang Q, DeFrain C, Osland J, Luo Y, Shi X and Yuan R: Suppressing NRIP1 inhibits growth of breast cancer cells in vitro and in vivo. Oncotarget. 6:39714–39724. 2015. View Article : Google Scholar : PubMed/NCBI
14	Huang CR, Jin ZX, Dong L, Tong XP, Yue S, Kawanami T, Sawaki T, Sakai T, Miki M, Iwao H, et al: Cisplatin augments FAS-mediated apoptosis through lipid rafts. Anticancer Res. 30:2065–2071. 2010.PubMed/NCBI
15	Zhang D, Wang Y, Dai Y, Wang J, Suo T, Pan H and Liu H, Shen S and Liu H: Downregulation of RIP140 in hepatocellular carcinoma promoted the growth and migration of the cancer cells. Tumour Biol. 36:2077–2085. 2015. View Article : Google Scholar : PubMed/NCBI
16	Jafari N, Zargar SJ, Yassa N and Delnavazi MR: Induction of apoptosis and cell cycle arrest by dorema glabrum root extracts in a gastric adenocarcinoma (AGS) cell line. Asian Pac J Cancer Prev. 17:5189–5193. 2016.PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Hu S, Ding Y, Gong J and Yan N: Sphingomyelin synthase 2 affects CD14-associated induction of NF-κB by lipopolysaccharides in acute lung injury in mice. Mol Med Rep. 14:3301–3306. 2016. View Article : Google Scholar : PubMed/NCBI
19	Berwick DC, Javaheri B, Wetzel A, Hopkinson M, Nixon-Abell J, Grannò S, Pitsillides AA and Harvey K: Pathogenic LRRK2 variants are gain-of-function mutations that enhance LRRK2-mediated repression of β-catenin signaling. Mol Neurodegener. 12:92017. View Article : Google Scholar : PubMed/NCBI
20	Sohda T, Iwata K, Hirano G, Sakurai K, Yokoyama K, Morihara D, Takeyama Y, Irie M, Shakado S and Sakisaka S: 3-Hydroxyl-3-methylglutaryl-coenzyme A reductase is up regulated in hepatocellular carcinoma associated with paraneoplastic hypercholesterolemia. Med Mol Morphol. 46:239–242. 2013. View Article : Google Scholar : PubMed/NCBI
21	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
22	Huang X, Ma J, Xu J, Su Q and Zhao J: Simvastatin induces growth inhibition and apoptosis in HepG2 and Huh7 hepatocellular carcinoma cells via upregulation of Notch1 expression. Mol Med Rep. 11:2334–2340. 2015. View Article : Google Scholar : PubMed/NCBI
23	Lee SJ, Hwang JW, Yim H, Yim HJ, Woo SU, Suh SJ, Hyun JJ, Jung SW, Koo JS, Kim JH, et al: Synergistic effect of simvastatin plus NS398 on inhibition of proliferation and survival in hepatocellular carcinoma cell line. J Gastroenterol Hepatol. 29:1299–1307. 2014. View Article : Google Scholar : PubMed/NCBI
24	Higashi T, Hayashi H, Kitano Y, Yamamura K, Kaida T, Arima K, Taki K, Nakagawa S, Okabe H, Nitta H, et al: Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma. Med Oncol. 33:1232016. View Article : Google Scholar : PubMed/NCBI
25	Kim W, Yoon JH, Kim JR, Jang IJ, Bang YJ, Kim YJ and Lee HS: Synergistic anti-tumor efficacy of lovastatin and protein kinase C-beta inhibitor in hepatocellular carcinoma. Cancer Chemother Pharmacol. 64:497–507. 2009. View Article : Google Scholar : PubMed/NCBI
26	Lei JJ, Peng RJ, Kuang BH, Yuan ZY, Qin T, Liu WS, Guo YM, Han HQ, Lian YF, Deng CC, et al: NOP14 suppresses breast cancer progression by inhibiting NRIP1/Wnt/β-catenin pathway. Oncotarget. 6:25701–25714. 2015. View Article : Google Scholar : PubMed/NCBI