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Extracellular signal-regulated kinase 1\2 and protein phosphatase 2A are involved in the antiproliferative activity of conjugated linoleic acid in MCF-7 cells

Published online by Cambridge University Press:  08 March 2007

Antonella Miglietta ,
Francesca Bozzo ,
Ludovica Gabriel ,
Claudia Bocca  and
Rosa Angela Canuto
Antonella Miglietta*
Affiliation:
Department of Experimental Medicine and Oncology, University of Turin, C. Raffaello 30, 10125, Turin, Italy
Francesca Bozzo
Affiliation:
Department of Experimental Medicine and Oncology, University of Turin, C. Raffaello 30, 10125, Turin, Italy
Ludovica Gabriel
Affiliation:
Department of Experimental Medicine and Oncology, University of Turin, C. Raffaello 30, 10125, Turin, Italy
Claudia Bocca
Affiliation:
Department of Experimental Medicine and Oncology, University of Turin, C. Raffaello 30, 10125, Turin, Italy
Rosa Angela Canuto
Affiliation:
Department of Experimental Medicine and Oncology, University of Turin, C. Raffaello 30, 10125, Turin, Italy
*
*Corresponding author: Dr Antonella Miglietta, fax +39 011 6707753, email [email protected]
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Abstract

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Conjugated linoleic acid (CLA) has protective properties in breast cancer. Here, we studied the mechanisms underlying the effects of CLA on MCF-7 breast cancer cell proliferation, especially in correlation with the involvement of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and protein phosphatase 2A (PP2A). CLA inhibits MCF-7 cell growth in a concentration- and time-dependent manner, without triggering apoptosis. In assessing expression levels of proteins that play obligatory roles in the ERK cascade, we evidenced that CLA down-regulated Raf-1 and decreased levels of phospho-ERK1/2, as well as c-myc expression. Increase in PP2A expression rates were additionally observed after CLA treatment of MCF-7 cells. The above effects, as well as CLA-induced inhibition of cell growth, were reversed by okadaic acid, a specific inhibitor of PP2A. Thus, PP2A likely participates in deactivation of ERK1/2, and its up-regulation may represent a novel mechanism for CLA-induced inhibition of cell proliferation.

Keywords

Conjugated linoleic acidMCF-7 cell lineExtracellular signal-regulated kinase 1/2protein phosphatase 2AProliferation
Type
Research Article
Information
British Journal of Nutrition , Volume 96 , Issue 1 , January 2006 , pp. 22 - 27
Copyright
Copyright © The Nutrition Society 2006

References

Adeyinka, A, Nui, Y, Cherlet, T, Snell, LWatson, P-H & Murphy, LCActivated mitogen-activated protein kinase expression during human breast tumorigenesis and breast cancer progression. Clin Cancer Res (2002) 8 1747–1753.Google ScholarPubMed
Belury, MAInhibition of carcinogenesis by conjugated linoleic acid: potential mechanisms of action. J Nutr (2002) 132 2995–2998.CrossRefGoogle ScholarPubMed
Belury, MA, Nickel, KP, Bird, CE & Wu, YDietary conjugated linoleic acid modulation of phorbol ester skin tumor promotion. Nutr Cancer (1996) 26 149–157.CrossRefGoogle ScholarPubMed
Boelsma, E, Hendriks, HF & Roza, LNutritional skin care: health effects of micronutrients and fatty acids. Am J Clin Nutr (2001) 73 853–864.CrossRefGoogle ScholarPubMed
Boldt, S, Weidle, UH & Kolch, WThe role of MAPK pathways in the action of chemotherapeutic drugs. Carcinogenesis (2002) 23 1831–1838.CrossRefGoogle ScholarPubMed
Brown, JM, Boysen, MS, Chung, S, Fabiyi, O, Morrison, RF, Mandrup, S & McIntosh, MKConjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines. J Biol Chem (2004) 279 26735–26747.CrossRefGoogle ScholarPubMed
Chang, F, Steelman, LS, Lee, JT, Shelton, JG, Navolanic, PM, Blalock, WL, Franklin, RA, & McCubrey, JASignal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia (2003) 17 1263–1293.CrossRefGoogle ScholarPubMed
Cohen, PThe regulation of protein function by multisite phosphorylation – a 25 year update. Trends Biochem Sci (2000) 25 596–601.CrossRefGoogle ScholarPubMed
Escrich, E, Solanas, M, Soler, M, Ruiz, de, Villa, MC, Sanchez, JA & Segura, RDietary polyunsaturated n-6 lipidseffects on the growth and fatty acid composition of rat mammary tumors. J Nutr Biochem (2001) 12 536–549.CrossRefGoogle Scholar
Garcia, A, Cayla, X, Guergnon, J, Dessauge, F, Hospital, V, Rebollo, MP, Fleischer, A & Rebollo, ASerine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis. Biochimie (2003) 85 721–726.CrossRefGoogle ScholarPubMed
Gopalakrishna, R, Gundimeda, U, Fontana, JA & Clarke, RDifferential distribution of protein phosphatase 2A in human breast carcinoma cell lines and itsrelation to estrogen receptor status. Cancer Lett (1999) 136 143–151.CrossRefGoogle ScholarPubMed
Gotz, J, Probst, A, Ehler, E, Hemmings, B & Kues, WDelayed embryonic lethality in mice lacking protein phosphatase 2A catalytic subunit C α. Proc Natl Acad Sci U S A (1998) 95 12370–12375.CrossRefGoogle Scholar
Ip, C, Carter, CA & Ip, MMRequirement of essential fatty acid for mammary tumorigenesis in the rat. Cancer Res (1985) 45 1997–2001.Google ScholarPubMed
Ip, C, Dong, Y, Ip, MM, Banni, S, Carta, G, Angioni, E, Murru, E, Spada, S, Melis, MP & Saebo, AConjugated linoleic acid isomers and mammary cancer prevention. Nutr Cancer (2002) 43 52–58.CrossRefGoogle ScholarPubMed
Ip, MM, Masso-Welch, PA, Shoemaker, SF, Shea-Eaton, WK & Ip, CConjugated linoleic acid inhibits proliferation and induces apoptosis of normal rat mammary epithelial cells in primary culture. Exp Cell Res (1999) 250 22–34.CrossRefGoogle ScholarPubMed
Jaattela, MMultiple cell death pathways as regulators of tumour initiation and progression. Oncogene (2004) 23 2746–2756.CrossRefGoogle ScholarPubMed
Janssens, V & Goris, JProtein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicatedin cell growth and signaling. Biochem J (2001) 353 417–439.CrossRefGoogle Scholar
Liu, X, Yan, S, Zhou, T, Terada, Y & Erikson, RLThe MAP kinase pathway is required for entry into mitosis and cell survival. Oncogene (2004) 23 763–776.CrossRefGoogle ScholarPubMed
Maggiora, M, Bologna, M & Ceru, MPAn overview of the effect of linoleic and conjugated-linoleic acids on the growth of several human tumor cell lines. Int J Cancer (2004) 12 909–919.CrossRefGoogle Scholar
ajumder, B, Wahle, KW, Moir, S, Schofield, A, Choe, SN, Farquharson, A, Grant, I & Heys, SDConjugated linoleic acids (CLAs) regulate the expression of key apoptotic genes in human breast cancer cells. FASEB J (2002) 16 1447–1449.CrossRefGoogle Scholar
Mawson, A, Lai, A, Carroll, JS, Sergio, CM, Mitchell, CJ & Sarcevic, BEstrogen and insulin/IGF-1 cooperatively stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-Myc and cyclin D1. Mol Cell Endocrinol (2005) 229 161–173.CrossRefGoogle ScholarPubMed
Miglietta, A, Bozzo, F, Bocca, C, Gabriel, L, Trombetta, A, Belotti, S & Canuto, RAConjugated linoleic acid induces apoptosis in MDA-MB-231 breast cancer cells through ERK/MAPK signalling and mitochondrial pathway. Cancer Lett (2006) 234 149–157.CrossRefGoogle ScholarPubMed
Muzio, G, Maggiora, M, Trombetta, A, Martinasso, G, Reffo, P, Colombatto, S & Canuto, RAMechanisms involved in growth inhibition induced by clofibrate in hepatoma cells. Toxicology (2003) 187 149–159.CrossRefGoogle ScholarPubMed
Ochoa, JJ, Farquharson, AJ, Grant, I, Moffat, LE, Heys, SD & Wahle, KWConjugated linoleic acids (CLA's) decrease prostate cancer cell proliferation: different molecular mechanisms for cis-9, trans-11 and trans-10, cis-12 isomers. Carcinogenesis (2004) 25 1185–1191.CrossRefGoogle Scholar
Park, Y, Allen, KG & Shultz, TDModulationof MCF-7 breast cancer cell signal transduction by linoleic acid and conjugated linoleic acid in culture. Anticancer Res (2000) 20 669–676.Google Scholar
Reyes, N, Reyes, I, Tiwari, R & Geliebter, JEffect of linoleic acid on proliferation and gene expression in the breast cancer cell line T47D. Cancer Lett (2004) 209 25–35.CrossRefGoogle ScholarPubMed
Santen, RJ, Song, RX, McPherson, R, Kumar, R, Adam, L, Jeng, MH & Yue, WThe role of mitogen-activated protein (MAP) kinase in breast cancer. J Steroid Biochem Mol Biol (2002) 80 239–256.CrossRefGoogle ScholarPubMed
Schonthal, AHRole of serine/threonine protein phosphatase 2A in cancer. Cancer Lett (2001) 170 1–13.CrossRefGoogle ScholarPubMed
Sebolt-Leopold, JS & Herrera, RTargeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer (2004) 4 937–947.CrossRefGoogle ScholarPubMed
Shultz, TD, Chew, BP & Seaman, WRDifferential stimulatory and inhibitory responses of human MCF-7 breast cancer cells to linoleic acid and conjugated linoleic acid in culture. Anticancer Res (1992) 12 2143–2145.Google ScholarPubMed
Stoll, BAN-3 fatty acids and lipid peroxidation in breast cancer inhibition. Br J Nutr (2002) 87 193–198.CrossRefGoogle ScholarPubMed
Whigham, LD, Cook, ME & Atkinson, RLConjugated linoleic acid: implications for human health. Pharmacol Res (2000) 42 503–510.CrossRefGoogle ScholarPubMed
Williams, R, Sanghera, J, Wu, F, Carbonaro-Hall, D, Campbell, DL, Warburton, D & Hall, FIdentification of a human epidermal growth factor receptor-associated protein kinase as a new member of the mitogen-activated protein kinase/extracellular signal-regulated protein kinase family. J Biol Chem (1993) 268 18213–18217.CrossRefGoogle ScholarPubMed
Zhang, L, Bewick, M & Lafrenie, RMRole of Raf-1 and FAK in cell density-dependent regulation of integrin-dependent activation of MAP kinase. Carcinogenesis (2002) 23 1251–1258.CrossRefGoogle ScholarPubMed
Zivadinovic, D & Watson, CSMembrane estrogen receptor-alpha levels predict estrogen-induced ERK1/2 activation in MCF-7 cells. Breast Cancer Res (2005) 7 R130–R144.CrossRefGoogle ScholarPubMed