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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 volume 26, pages 5046–5059 (2007)Cite this article

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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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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  1. H Lue and M Thiele: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Cell Biology, Institute of Biochemistry, University Hospital RWTH Aachen, Aachen, Germany

    H Lue, M Thiele, J Franz & J Bernhagen

  2. Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany

    E Dahl

  3. Department of Biochemistry and Molecular Biology, Institute of Biochemistry, University Hospital RWTH Aachen, Aachen, Germany

    S Speckgens & B Lüscher

  4. Department of Medicine and Pathology, Yale University, School of Medicine, New Haven, USA

    L Leng & R Bucala

  5. Medical Clinic I, University Hospital Cologne, Cologne, Germany

    G Fingerle-Rowson

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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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