Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression
- 426 Downloads
Different agents able to modulate apoptosis have been shown to modify the expression of the MAP-kinase-phosphatase-1 (MKP-1). The expression of this phosphatase has been considered a potential positive prognostic factor in lung cancer, and smoke was shown to reduce the levels of MKP-1 in ferret lung. Our aim was to assess whether the n-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), known to inhibit the growth of several cancer cells mainly inducing apoptosis, may exert pro-apoptotic effect in lung cancer cells by modifying MKP-1 expression. We observed that DHA increased MKP-1 protein and mRNA expression and induced apoptosis in different lung cancer cell lines (mink Mv1Lu adenocarcinoma cells, human A549 adenocarcinoma and human BEN squamous carcinoma cells). We inhibited the pro-apoptotic effect of DHA by treating the cells with the phosphatase inhibitor Na3VO4 or by silencing the MKP-1 gene with the specific siRNA. This finding demonstrated that the induction of apoptosis by DHA involved a phosphatase activity, specifically that of MKP-1. DHA reduced also the levels of the phosphorylated MAP-kinases, especially ERK1/2 and p38. Such an effect was not observed when the MKP-1 gene was silenced. Altogether, the data provide evidence that the DHA-induced overexpression of MKP-1 and the resulting decrease of MAP-kinase phosphorylation by DHA may underlie the pro-apoptotic effect of this fatty acid in lung cancer cells. Moreover, they support the hypothesis that DHA may exert chemopreventive action in lung cancer.
Key wordsApoptosis Docosahexaenoic acid Lung cancer cells MAP kinases MKP-1
This work was supported in part by grant D1 2006 to GC from the Catholic University of Sacred Hearth within its program of promotion and diffusion of scientific research.
- 3.Calviello G, Di Nicuolo F, Gragnoli S, Piccioni E, Serini S, Maggiano N et al (2004) n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE2 induced ERK-1 and -2 and HIF-1alpha induction pathway. Carcinogenesis 25:2303–2310. doi: 10.1093/carcin/bgh265 PubMedCrossRefGoogle Scholar
- 6.Calviello G, Resci F, Serini S, Piccioni E, Toesca A, Boninsegna A et al (2007) Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2. Carcinogenesis 28:1202–1209. doi: 10.1093/carcin/bgl254 PubMedCrossRefGoogle Scholar
- 18.Vicent S, Garayoa M, Lopez-Picazo JM, Lozano MD, Toledo G, Thunnissen FB et al (2004) Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell lung cancer and is an independent predictor of outcome in patients. Clin Cancer Res 10:3639–3649. doi: 10.1158/1078-0432.CCR-03-0771 PubMedCrossRefGoogle Scholar
- 26.Engelbrecht AM, Engelbrecht P, Genade S, Niesler C, Page C, Smuts M et al (2005) Long-chain polyunsaturated fatty acids protect the heart against ischemia/reperfusion-induced injury via a MAPK dependent pathway. J Mol Cell Cardiol 39:940–954. doi: 10.1016/j.yjmcc.2005.08.004 PubMedCrossRefGoogle Scholar
- 32.Yusufi AN, Cheng J, Thompson MA, Walker HJ, Gray CE, Warner GM et al (2003) Differential effects of low-dose docosahexaenoic acid and eicosapentaenoic acid on the regulation of mitogenic signaling pathways in mesangial cells. J Lab Clin Med 141:318–329. doi: 10.1016/S0022-2143(03)00005-2 PubMedCrossRefGoogle Scholar
- 40.Payne M, Ellis P, Dunlop D, Ranson M, Danson S, Schacter L et al (2006) DHA-paclitaxel (Taxoprexin) as first-line treatment in patients with stage IIIB or IV non-small cell lung cancer: report of a phase II open-label multicenter trial. J Thorac Oncol 1:984–990. doi: 10.1097/01243894-200611000-00011 PubMedCrossRefGoogle Scholar
- 43.Gorman A, McCarthy J, Finucane D, Reville W, Cotter TG (1996) In: Cotter TG, Martin SJ (eds) Techniques in apoptosis. Portland Press Ltd., London, pp 7–9Google Scholar
- 48.Chen YL, Lin PC, Chen SP, Lin CC, Tsai NM, Cheng YL et al (2007) Activation of NAG-1 via ERK1/2 mitogen-activated protein kinase revealed a isochaihulactone-triggered apoptotic pathway in human lung cancer A549 cells. J Pharmacol Exp Ther 323:746–756. doi: 10.1124/jpet.107.126193 PubMedCrossRefGoogle Scholar
- 57.Aires V, Hichami A, Filomenko R, Plé A, Rébé C, Bettaieb A, Khan NA (2007) Docosahexaenoic acid induces increases in [Ca2+]i via inositol 1,4,5-triphosphate production and activates protein kinase C gamma and -delta via phosphatidylserine binding site: implication in apoptosis in U937 cells. Mol Pharmacol 72:1545–1556PubMedCrossRefGoogle Scholar
- 62.Danbara N, Yuri T, Tsujita-Kyutoku M, Sato M, Senzaki H, Takada H, Hada T, Miyazawa T, Okazaki K, Tsubura A (2004) Conjugated docosahexaenoic acid is a potent inducer of cell cycle arrest and apoptosis and inhibits growth of colo 201 human colon cancer cells. Nutr Cancer 50:71–79PubMedCrossRefGoogle Scholar