Abstract
The phosphoinositide-3-kinase (PI3K)/Akt signaling pathway plays an important role in cell survival and the development of cancer. Macrophage migration inhibitory factor (MIF) is a critical inflammatory cytokine that was recently associated with tumorigenesis and that potently inhibits apoptosis. This may involve inhibition of p53-dependent genes, but the initiating molecular mechanism of how MIF controls survival/apoptosis is unknown. Here, we show that MIF prevents apoptosis and promotes tumor cell survival by directly activating the Akt pathway. MIF enhanced Akt activity in primary and immortalized fibroblasts (MEF and NIH/3T3), HeLa cervix carcinoma cells and various breast cancer cell lines. Activation was abolished by kinase inhibitors Ly294002 and PP2 and in Src/Yes/Fyn(SYF)−/− and CD74−/−(MEFs), while being enhanced in CD74-overexpressing MEFs, demonstrating that the MIF-induced Akt pathway encompasses signaling through the MIF receptor CD74 and the upstream kinases Src and PI3K. Akt was activated by exogenous rMIF and autocrine MIF action, as revealed by experiments in MIF−/−MEFs and antibody blockade. siRNA knockdown of CSN5/JAB1, a tumor marker and MIF-binding protein, showed that JAB1 controls autocrine MIF-mediated Akt signaling by inhibition of MIF secretion. Akt activation by MIF led to phosphorylation of the proapoptotic proteins BAD and Foxo3a. Apoptosis inhibition by MIF was functionally associated with Akt activation as it was abolished by overexpression of the Akt pathway inhibitor PTEN and occurred independently of p53. This was shown by studying DNA damage-induced apoptosis in fibroblasts, the Fas death pathway in HeLa cells that do not express functional p53, and etoposide-induced apoptosis in breast carcinoma cells expressing mutant p53. Importantly, dependence of breast cancer cell survival on MIF correlated with Akt activation and the PTEN status of these cells. Thus, MIF can directly promote cell survival through activation of the PI3K/Akt pathway and this effect is critical for tumor cell survival.
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References
Adler AS, Lin M, Horlings H, Nuyten DS, van de Vijver MJ, Chang HY . (2006). Genetic regulators of large-scale transcriptional signatures in cancer. Nat Genet 38: 421–430.
Alessi DR, Cohen P . (1998). Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev 8: 55–62.
Amin MA, Haas CS, Zhu K, Mansfield PJ, Kim MJ, Lackowski NP et al. (2005). Migration inhibitory factor upregulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 via Src, PI3 kinase, and NFkappaB. Blood 107: 2252–2261.
Amin MA, Volpert OV, Woods JM, Kumar P, Harlow LA, Koch AE . (2003). MIF mediates angiogenesis via mitogen-activated protein kinase and phosphatidylinositol kinase. Circ Res 93: 321–329.
Bando H, Matsumoto G, Bando M, Muta M, Ogawa T, Funata N et al. (2002). Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread. JPN J Cancer Res 93: 389–396.
Bech-Otschir D, Seeger M, Dubiel W . (2002). The COP9 signalosome: at the interface between signal transduction and ubiquitin-dependent proteolysis. J Cell Sci 115: 467–473.
Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W et al. (1993). MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365: 756–759.
Brazil DP, Park J, Hemmings BA . (2002). PKB binding proteins. Getting in on the Akt. Cell 111: 293–303.
Burger-Kentischer A, Finkelmeier D, Thiele M, Schmucker J, Geiger G, Tovar GE et al. (2005). Binding of JAB1/CSN5 to MIF is mediated by the MPN domain but is independent of the JAMM motif. FEBS Lett 579: 1693–1701.
Byrne AM, Bouchier-Hayes DJ, Harmey JH . (2005). Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 9: 777–794.
Calandra T, Roger T . (2003). Macrophage migration inhibitory factor: A regulator of innate immunity. Nat Rev Immunol 3: 791–800.
Chamovitz DA, Segal D . (2001). JAB1/CSN5 and the COP9 signalosome. A complex situation. EMBO Rep 2: 96–101.
Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL et al. (2003). Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17: 590–603.
Cheng JQ, Lindsley CW, Cheng GZ, Yang H, Nicosia SV . (2005). The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 24: 7482–7492.
Chesney J, Metz C, Bacher M, Peng T, Meinhardt A, Bucala R . (1999). An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma. Mol Med 5: 181–191.
Datta SR, Ranger AM, Lin MZ, Sturgill JF, Ma YC, Cowan CW et al. (2002). Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev Cell 3: 631–643.
DeGraffenried LA, Fulcher L, Friedrichs WE, Grunwald V, Ray RB, Hidalgo M . (2004). Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. Ann Oncol 15: 1510–1516.
Fingerle-Rowson G, Petrenko O, Metz CN, Forsthuber TG, Mitchell R, Huss R et al. (2003). The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc Natl Acad Sci USA 100: 9354–9359.
Flieger O, Engling A, Bucala R, Lue H, Nickel W, Bernhagen J . (2003). Regulated secretion of macrophage migration inhibitory factor is mediated by a non-classical pathway involving an ABC transporter. FEBS Lett 551: 78–86.
Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, Charles K et al. (2005). Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol 175: 1197–1205.
Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB . (2005). Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4: 988–1004.
Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH . (1999). A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med 190: 1375–1382.
Kleemann R, Hausser A, Geiger G, Mischke R, Burger-Kentischer A, Flieger O et al. (2000). Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408: 211–216.
Koyasu S . (2003). The role of PI3K in immune cells. Nat Immunol 4: 313–319.
Leng L, Metz CN, Fang YXJ, Donnelly S, Baugh J, Delohery T et al. (2003). MIF signal transduction initiated by binding to CD74. J Exp Med 197: 1467–1476.
Lue H, Kapurniotu A, Fingerle-Rowson G, Roger T, Leng L, Thiele M et al. (2006). Rapid and transient activation of the ERK MAPK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on JAB1/CSN5 and Src kinase activity. Cell Signal 18: 688–703.
Mitchell RA . (2004). Mechanisms and effectors of MIF-dependent promotion of tumourigenesis. Cell Signal 16: 13–19.
Mitchell RA, Bucala R . (2000). Tumor growth-promoting properties of macrophage migration inhibitory factor. Semin Cancer Biol 10: 359–366.
Mitchell RA, Liao H, Chesney J, Fingerle-Rowson G, Baugh J, David J et al. (2002). Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: Regulatory role in the innate immune response. Proc Natl Acad Sci USA 99: 345–350.
Mitchell RA, Metz CN, Peng T, Bucala R . (1999). Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action. J Biol Chem 274: 18100–18106.
Morand EF, Leech M, Bernhagen J . (2006). MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis. Nat Rev Drug Discov 5: 399–410.
Nguyen M, Lue H, Kleemann R, Thiele M, Tolle G, Finkelmeier D et al. (2003). The cytokine macrophage migration inhibitory factor (MIF) reduces pro-oxidative stress-induced apoptosis. J Immunol 170: 3337–3347.
Nickel W . (2003). The mystery of nonclassical protein secretion. A current view on cargo proteins and potential export routes. Eur J Biochem 270: 2109–2119.
Nishihira J, Ishibashi T, Fukushima T, Sun B, Sato Y, Todo S . (2003). Macrophage migration inhibitory factor (MIF): Its potential role in tumor growth and tumor-associated angiogenesis. Ann N Y Acad Sci 995: 171–182.
Osaki M, Oshimura M, Ito H . (2004). PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 9: 667–676.
Osoegawa A, Yoshino I, Kometani T, Yamaguchi M, Kameyama T, Yohena T et al. (2006). Overexpression of Jun activation domain-binding protein 1 in nonsmall cell lung cancer and its significance in p27 expression and clinical features. Cancer 107: 154–161.
Perren A, Weng LP, Boag AH, Ziebold U, Thakore K, Dahia PL et al. (1999). Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol 155: 1253–1260.
Schober A, Bernhagen J, Thiele M, Zeiffer U, Knarren S, Roller M et al. (2004). Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice. Circulation 109: 380–385.
Shi X, Leng L, Wang T, Wang W, Du X, Li J et al. (2006). CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity 25: 595–606.
Shimizu T, Abe R, Nakamura H, Ohkawara A, Suzuki M, Nishihira J . (1999). High expression of macrophage migration inhibitory factor in human melanoma cells and its role in tumor cell growth and angiogenesis. Biochem Biophys Res Commun 264: 751–758.
Shiojima I, Walsh K . (2002). Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90: 1243–1250.
Song G, Ouyang G, Bao S . (2005). The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9: 59–71.
Sun H, Bernhagen J, Bucala R, Lolis E . (1996). Crystal structure at 2.6 Å resolution of human macrophage migration inhibitory factor. Proc Natl Acad Sci USA 93: 5191–5196.
Takahashi N, Nishihira J, Sato Y, Kondo M, Ogawa H, Ohshima T et al. (1998). Involvement of macrophage migration inhibitory factor (MIF) in the mechanism of tumor cell growth. Mol Med 4: 707–714.
Tomoda K, Kubota Y, Kato J-Y . (1999). Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature 398: 160–164.
Veeck J, Niederacher D, An H, Klopocki E, Wiesmann F, Betz B et al. (2006). Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis. Oncogene 25: 3479–3488.
Wetzker R, Bohmer FD . (2003). Transactivation joins multiple tracks to the ERK/MAPK cascade. Nat Rev Mol Cell Biol 4: 651–657.
Wolf DA, Zhou C, Wee S . (2003). The COP9 signalosome: an assembly and maintenance platform for cullin ubiquitin ligases ? Nat Cell Biol 5: 1029–1033.
Zapata JM, Krajewska M, Krajewski S, Huang RP, Takayama S, Wang HG et al. (1998). Expression of multiple apoptosis-regulatory genes in human breast cancer cell lines and primary tumors. Breast Cancer Res Treat 47: 129–140.
Acknowledgements
We are grateful to E Bianchi, C Weber, H Fünfzig, and A Kapurniotu for helpful discussions and to S Schwemmers and Inge Losen for technical help with the FOXO analysis and breast cancer cell cultivation, respectively. Supported by DFG grants SFB542/TP-A7 and SFB542/TP-B8 and START-grant 696055/53 to JB and BL, respectively, by START-grant 696050 to ED, by NIH grants AI43210 and AR49610 to RB, and by grants 145/2004 (Köln-Fortune) and FI 712/2-1 (DFG) to GFR.
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Lue, H., Thiele, M., Franz, J. et al. Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. Oncogene 26, 5046–5059 (2007). https://doi.org/10.1038/sj.onc.1210318
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DOI: https://doi.org/10.1038/sj.onc.1210318
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