Telmisartan prevents proliferation and promotes apoptosis of human ovarian cancer cells through upregulating PPARγ and downregulating MMP‑9 expression

Pu,Zhichen; Zhu,Min; Kong,Fandou

doi:10.3892/mmr.2015.4512

Telmisartan prevents proliferation and promotes apoptosis of human ovarian cancer cells through upregulating PPARγ and downregulating MMP‑9 expression

Authors:
- Zhichen Pu
- Min Zhu
- Fandou Kong
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Affiliations: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
Published online on: November 6, 2015 https://doi.org/10.3892/mmr.2015.4512
Pages: 555-559

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Abstract

The mortality rate of ovarian cancer is the highest of all gynecological malignancies. Telmisartan is a commonly used clinical angiotensin receptor blocker, which has antihypertensive, anti‑inflammatory and antithrombotic effects. In the present study, it was investigated whether telmisartan could exert anticancer effects on ovarian cancer cells through upregulating peroxisome proliferator‑activated receptor γ (PPARγ) and downregulating matrix metalloproteinase‑9 (MMP‑9) expression. A 3.3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was conducted to analyze the proliferation of HEY cells. A Caspase‑3 Activity Assay kit and an Annexin V‑fluorescein isothiocyanate/propidium iodide kit were used to analyze the apoptosis of HEY cells. In addition, a gelatin zymography assay and reverse trancription‑quantitative polymerase chain reaction were included to analyze the expression of PPARγ and MMP‑9 in HEY cells. The data showed that telmisartan could significantly decrease cell viability and induce the apoptosis of HEY cells in a time‑ and dose‑dependent manner. Furthermore, telmisartan could also dose‑dependently increase the expression of PPARγ and decrease the expression of MMP‑9 in HEY cells. In addition, downregulation of the expression of PPARγ by small interfering (si)RNA could reduce the effect of telmisartan on ovarian cancer cells and increase the expression of MMP‑9. In conclusion, the results indicated that telmisartan prevents proliferation and promotes apoptosis of human ovarian cancer cells by upregulating PPARγ and downregulating MMP‑9 expression.

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1	Kamangar F, Dores GM and Anderson WF: Patterns of cancer incidence, mortality and prevalence across five continents: Defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 24:2137–2150. 2006. View Article : Google Scholar : PubMed/NCBI
2	Des Jarlais G, Kaplan CP, Haas JS, Gregorich SE, Pérez-Stable EJ and Kerlikowske K: Factors affecting participation in a breast cancer risk reduction telephone survey among women from four racial/ethnic groups. Prev Med. 41:720–727. 2005. View Article : Google Scholar : PubMed/NCBI
3	Salehi F, Dunfield L, Phillips KP, Krewski D and Vanderhyden BC: Risk factors for ovarian cancer: An overview with emphasis on hormonal factors. J Toxicol Environ Health B Crit Rev. 11:301–321. 2008. View Article : Google Scholar : PubMed/NCBI
4	Vo C and Carney ME: Ovarian cancer hormonal and environmental risk effect. Obstet Gynecol Clin North Am. 34:687–700. viii2007. View Article : Google Scholar : PubMed/NCBI
5	Xie Y, Zhu J, Zhou XJ, Chen J, Lu NH and Wang CW: Expression of peroxisome proliferators-activated receptor-gamma and cyclooxygenase-2 in Helicobacter pylori infection-associated diseases and significance thereof. Zhonghua Yi Xue Za Zhi. 86:2683–2689. 2006.In Chinese.
6	DuBois RN, Gupta R, Brockman J, Reddy BS, Krakow SL and Lazar MA: The nuclear eicosanoid receptor, PPARgamma, is aberrantly expressed in colonic cancers. Carcinogenesis. 19:49–53. 1998. View Article : Google Scholar : PubMed/NCBI
7	Jiang WG, Redfern A, Bryce RP and Mansel RE: Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells. Prostaglandins Leukot Essent Fatty Acids. 62:119–127. 2000. View Article : Google Scholar : PubMed/NCBI
8	Wijnhoven BP, Lindstedt EW, Abbou M, Ijzendoorn Y, de Krijger RR, Tilanus HW and Dinjens WN; Rotterdam Esophageal Tumor Study Group: Molecular genetic analysis of the von Hippel-Lindau and human peroxisome proliferator-activated receptor gamma tumor-suppressor genes in adenocarcinomas of the gastroesophageal junction. Int J Cancer. 94:891–895. 2001. View Article : Google Scholar : PubMed/NCBI
9	Chang TH and Szabo E: Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in non-small cell lung cancer. Cancer Res. 60:1129–1138. 2000.PubMed/NCBI
10	Papi A, De Carolis S, Bertoni S, Storci G, Sceberras V, Santini D, Ceccarelli C, Taffurelli M, Orlandi M and Bonafé M: PPARγ and RXR ligands disrupt the inflammatory cross-talk in the hypoxic breast cancer stem cells niche. J Cell Physiol. 229:1595–1606. 2014. View Article : Google Scholar : PubMed/NCBI
11	Chatterjee A, Kusunoki H, Taniyama Y, Rakugi H and Morishita R: Improvement of metabolic syndrome by irbesartan via the PPARγ/HGF pathway in apolipoprotein E knockout mice. Biomed Rep. 1:65–70. 2013.PubMed/NCBI
12	Łukaszewicz-Zając M, Mroczko B, Guzińska-Ustymowicz K, Pryczynicz A, Gryko M, Kemona A, Kędra B and Szmitkowski M: Matrix metalloproteinase 2 (MMP-2) and their tissue inhibitor 2 (TIMP-2) in gastric cancer patients. Adv Med Sci. 58:235–243. 2013. View Article : Google Scholar
13	Waite LL, Louie RE and Taylor RN: Circulating activators of peroxisome proliferator-activated receptors are reduced in preeclamptic pregnancy. J Clin Endocrinol Metab. 90:620–626. 2005. View Article : Google Scholar
14	Liu J, Lu H, Huang R, Lin D, Wu X, Lin Q, Wu X, Zheng J, Pan X, Peng J, et al: Peroxisome proliferator activated receptor-gamma ligands induced cell growth inhibition and its influence on matrix metalloproteinase activity in human myeloid leukemia cells. Cancer Chemother Pharmacol. 56:400–408. 2005. View Article : Google Scholar : PubMed/NCBI
15	Balakumar P, Bishnoi HK and Mahadevan N: Telmisartan in the management of diabetic nephropathy: A contemporary view. Curr Diabetes Rev. 8:183–190. 2012. View Article : Google Scholar : PubMed/NCBI
16	Takagi H, Mizuno Y, Yamamoto H, Goto SN and Umemoto T; All-Literature Investigation of Cardiovascular Evidence Group: Effects of telmisartan therapy on interleukin-6 and tumor necrosis factor-alpha levels: A meta-analysis of randomized controlled trials. Hypertens Res. 36:368–373. 2013. View Article : Google Scholar
17	Lacourcière Y: Telmisartan or valsartan alone or in combination with hydrochlorothiazide: A review. Clin Exp Hypertens. 35:50–60. 2013. View Article : Google Scholar
18	Maejima Y, Okada H, Haraguchi G, Onai Y, Kosuge H, Suzuki J and Isobe M: Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma. Lab Invest. 91:932–944. 2011. View Article : Google Scholar : PubMed/NCBI
19	Li J, Chen L, Yu P, Liu B, Zhu J and Yang Y: Telmisartan exerts anti-tumor effects by activating peroxisome proliferator-activated receptor-γ in human lung adenocarcinoma A549 cells. Molecules. 19:2862–2876. 2014. View Article : Google Scholar : PubMed/NCBI
20	Shi M, Cao M, Song J, Liu Q, Li H, Meng F, Pan Z, Bai J and Zheng J: PinX1 inhibits the invasion and metastasis of human breast cancer via suppressing NF-κB/MMP-9 signaling pathway. Mol Cancer. 14:662015. View Article : Google Scholar
21	Mozzetti S, Ferlini C, Concolino P, Filippetti F, Raspaglio G, Prislei S, Gallo D, Martinelli E, Ranelletti FO, Ferrandina G and Scambia G: Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. Clin Cancer Res. 11:298–305. 2005.PubMed/NCBI
22	Kamat AA, Kim TJ, Landen CN Jr, Lu C, Han LY, Lin YG, Merritt WM, Thaker PH, Gershenson DM, Bischoff FZ, et al: Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. Cancer Res. 67:281–288. 2007. View Article : Google Scholar : PubMed/NCBI
23	de Araújo Júnior RF, Leitão Oliveira AL, de Melo Silveira RF, de Oliveira Rocha HA, de França Cavalcanti P and de Araújo AA: Telmisartan induces apoptosis and regulates Bcl-2 in human renal cancer cells. Exp Biol Med (Maywood). 240:34–44. 2015. View Article : Google Scholar
24	Koyama N, Nishida Y, Ishii T, Yoshida T, Furukawa Y and Narahara H: Telmisartan induces growth inhibition, DNA double-strand breaks and apoptosis in human endometrial cancer cells. PLoS One. 9:e930502014. View Article : Google Scholar : PubMed/NCBI
25	Auwerx J: PPARgamma, the ultimate thrifty gene. Diabetologia. 42:1033–1049. 1999. View Article : Google Scholar : PubMed/NCBI
26	Komar CM: Peroxisome proliferator-activated receptors (PPARs) and ovarian function-implications for regulating steroidogenesis, differentiation and tissue remodeling. Reprod Biol Endocrinol. 3:412005. View Article : Google Scholar
27	Kolli V, Stechschulte LA, Dowling AR, Rahman S, Czernik PJ and Lecka-Czernik B: Partial agonist, telmisartan, maintains PPARγ serine 112 phosphorylation, and does not affect osteoblast differentiation and bone mass. PLoS One. 9:e963232014. View Article : Google Scholar
28	Pang T, Sun LX, Wang T, Jiang ZZ, Liao H and Zhang LY: Telmisartan protects central neurons against nutrient deprivation-induced apoptosis in vitro through activation of PPARγ and the Akt/GSK-3 β pathway. Acta Pharmacol Sin. 35:727–737. 2014. View Article : Google Scholar : PubMed/NCBI
29	Yiqin Y, Meilin X, Jie X and Keping Z: Aspirin inhibits MMP-2 and MMP-9 expression and activity through PPARalpha/gamma and TIMP-1-mediated mechanisms in cultured mouse celiac macrophages. Inflammation. 32:233–241. 2009. View Article : Google Scholar : PubMed/NCBI
30	Funao K, Matsuyama M, Kawahito Y, Sano H, Chargui J, Touraine JL, Nakatani T and Yoshimura R: Telmisartan as a peroxisome proliferator-activated receptor-γ ligand is a new target in the treatment of human renal cell carcinoma. Mol Med Rep. 2:193–198. 2009.PubMed/NCBI
31	Zafiriou S, Stanners SR, Saad S, Polhill TS, Poronnik P and Pollock CA: Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts. J Am Soc Nephrol. 16:638–645. 2005. View Article : Google Scholar : PubMed/NCBI
32	Araújo AA, Souza TO, Moura LM, Brito GA, Aragão KS, Araújo LS, Medeiros CA, Alves MS and Araújo RF Jr: Effect of telmisartan on levels of IL-1, TNF-α, down-regulated COX-2, MMP-2, MMP-9 and RANKL/RANK in an experimental periodontitis model. J Clin Periodontol. 40:1104–1111. 2013. View Article : Google Scholar
33	Yokota T, Osanai T, Hanada K, Kushibiki M, Abe N, Oikawa K, Tomita H, Higuma T, Yokoyama J, Hanada H and Okumura K: Effects of telmisartan on markers of ventricular remodeling in patients with acute myocardial infarction: Comparison with enalapril. Heart Vessels. 25:460–468. 2010. View Article : Google Scholar : PubMed/NCBI
34	Wu J, Lin H, Liu D, Liu J, Wang N, Mei X, Sun J, Yang G and Zhang X: The protective effect of telmisartan in Type 2 diabetes rat kidneys is related to the downregulation of thioredoxin-interacting protein. J Endocrinol Invest. 36:453–459. 2013.