Olive Oil Polyphenols Differentially Inhibit Smooth Muscle Cell Proliferation through a G1/S Cell Cycle Block Regulated by ERK1/2

Abstract

We hypothesized that polyphenols contained in olive oil play a role in reducing the risk of atherosclerosis. The aim of this study was to determine if the polyphenols in olive oil, oleuropein (Ole), hydroxytyrosol (HT), and tyrosol (Tyr) could inhibit smooth muscle cell (SMC) proliferation through its influence on cell cycle regulation. Bovine vascular SMC were cultured in the presence of Ole, HT, or Tyr at concentration of 1, 10, or 100 μmol/L. On days 1, 3, and 5, numbers of cells were counted. Cell cycle analysis was performed by flow cytometry on day 1 after SMC were stained with propidium iodide. Cell populations grown in the presence of Ole or HT at 100 μmol/L concentration were significantly inhibited after 5 days of exposure. Tyr had a similar tendency but it did not attain significance. Cell cycle analysis revealed that 66% of cells were in G1 phase in Ole group, compared with 48% in control group. To examine the cell cycle block between G1 and S phases, we performed Western blotting and found that ERK1/2 activation was inhibited by Ole or HT. We conclude that olive oil polyphenols could inhibit SMC proliferation through a cell cycle block between G1 and S phases which may be regulated by ERK1/2. These results demonstrate a mechanism by which olive oil consumption may be atheroprotective by inhibiting SMC proliferation.

Keywords

olive oil - oleuropein - hydroxytyrosol - tyrosol - smooth muscle cell proliferation - ERK1/2

Note

This study was supported in part by NIH R01 HL-47345.

• References

• 1 Owen RW, Giacosa A, Hull WE , et al. Olive-oil consumption and health: the possible role of antioxidants. Lancet Oncol 2000; 1: 107-112
• 2 Huang CL, Sumpio BE. Olive oil, the mediterranean diet, and cardiovascular health. J Am Coll Surg 2008; 207 (3) 407-416
• 3 Cordova AC, Jackson LS, Berke-Schlessel DW, Sumpio BE. The cardiovascular protective effect of red wine. J Am Coll Surg 2005; 200 (3) 428-439
• 4 Poussier B, Cordova AC, Becquemin JP, Sumpio BE. Resveratrol inhibits vascular smooth muscle cell proliferation and induces apoptosis. J Vasc Surg 2005; 42 (6) 1190-1197
• 5 Fabiani R, Rosignoli P, De Bartolomeo A, Fuccelli R, Morozzi G. Inhibition of cell cycle progression by hydroxytyrosol is associated with upregulation of cyclin-dependent protein kinase inhibitors p21(WAF1/Cip1) and p27(Kip1) and with induction of differentiation in HL60 cells. J Nutr 2008; 138 (1) 42-48
• 6 Lee B, Lee EJ, Kim DI, Park SK, Kim WJ, Moon SK. Inhibition of proliferation and migration by piceatannol in vascular smooth muscle cells. Toxicol In Vitro 2009; 23 (7) 1284-1291
• 7 Meloche S, Pouysségur J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 2007; 26 (22) 3227-3239
• 8 Torii S, Yamamoto T, Tsuchiya Y, Nishida E. ERK MAP kinase in G cell cycle progression and cancer. Cancer Sci 2006; 97 (8) 697-702
• 9 Lopez-Miranda J, Delgado-Lista J, Perez-Martinez P , et al. Olive oil and the haemostatic system. Mol Nutr Food Res 2007; 51 (10) 1249-1259
• 10 Carluccio MA, Siculella L, Ancora MA , et al. Olive oil and red wine antioxidant polyphenols inhibit endothelial activation: antiatherogenic properties of Mediterranean diet phytochemicals. Arterioscler Thromb Vasc Biol 2003; 23 (4) 622-629
• 11 Corona G, Deiana M, Incani A, Vauzour D, Dessì MA, Spencer JP. Hydroxytyrosol inhibits the proliferation of human colon adenocarcinoma cells through inhibition of ERK1/2 and cyclin D1. Mol Nutr Food Res 2009; 53 (7) 897-903
• 12 D'Archivio M, Filesi C, Di Benedetto R, Gargiulo R, Giovannini C, Masella R. Polyphenols, dietary sources and bioavailability. Ann Ist Super Sanita 2007; 43 (4) 348-361
• 13 Singh N, Nigam M, Ranjan V, Zaidi D, Garg VK, Sharma S , et al. Resveratrol as an adjunct therapy in cyclophosphamide-treated MCF-7 cells and breast tumor explants. Cancer Sci 2011; 102 (5) 1059-1067
• 14 Han J, Talorete TP, Yamada P, Isoda H. Anti-proliferative and apoptotic effects of oleuropein and hydroxytyrosol on human breast cancer MCF-7 cells. Cytotechnology 2009; 59 (1) 45-53
• 15 Corona G, Deiana M, Incani A, Vauzour D, Dessì MA, Spencer JP. Inhibition of p38/CREB phosphorylation and COX-2 expression by olive oil polyphenols underlies their anti-proliferative effects. Biochem Biophys Res Commun 2007; 362 (3) 606-611
• 16 Bai Y, Mao QQ, Qin J , et al. Resveratrol induces apoptosis and cell cycle arrest of human T24 bladder cancer cells in vitro and inhibits tumor growth in vivo. Cancer Sci 2010; 101 (2) 488-493
• 17 Sirianni R, Chimento A, De Luca A , et al. Oleuropein and hydroxytyrosol inhibit MCF-7 breast cancer cell proliferation interfering with ERK1/2 activation. Mol Nutr Food Res 2010; 54 (6) 833-840
• 18 Roy P, Kalra N, Prasad S, George J, Shukla Y. Chemopreventive potential of resveratrol in mouse skin tumors through regulation of mitochondrial and PI3K/AKT signaling pathways. Pharm Res 2009; 26 (1) 211-217
• 19 Madan E, Prasad S, Roy P, George J, Shukla Y. Regulation of apoptosis by resveratrol through JAK/STAT and mitochondria mediated pathway in human epidermoid carcinoma A431 cells. Biochem Biophys Res Commun 2008; 377 (4) 1232-1237
• 20 Fitó M, de la Torre R, Farré-Albaladejo M, Khymenetz O, Marrugat J, Covas MI. Bioavailability and antioxidant effects of olive oil phenolic compounds in humans: a review. Ann Ist Super Sanita 2007; 43 (4) 375-381
• 21 Menendez JA, Vazquez-Martin A, Garcia-Villalba R , et al. tabAnti-HER2 (erbB-2) oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO). BMC Cancer 2008; 8: 377