Linking inflammation and neuroendocrine differentiation: the role of macrophage migration inhibitory factor-mediated signaling in prostate cancer

in Endocrine-Related Cancer
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  • 1 Departments of Urology, Biochemistry and Molecular Medicine, VA Northern California Health Care System, University of California Davis, Sacramento, California, USA

A new paper by Tawadros et al. in Endocrine-Related Cancer demonstrates a link between macrophage migration inhibitory factor and neuroendocrine differentiation in prostate cancer. This paper may have implications in explaining the effect of prostatitis and chronic inflammation on the development of aggressive prostate cancer.

Abstract

A new paper by Tawadros et al. in Endocrine-Related Cancer demonstrates a link between macrophage migration inhibitory factor and neuroendocrine differentiation in prostate cancer. This paper may have implications in explaining the effect of prostatitis and chronic inflammation on the development of aggressive prostate cancer.

Prostatitis, or inflammation of the prostate, may occur in men as young as 40, or even younger, while prostate cancer and benign prostatic hyperplasia (BPH, or enlargement of the prostate) are most often diagnosed in men above 50. While prostatitis has never been formally established as a cause of prostate cancer, very often men who suffer from prostatitis tend to develop prostate cancer later on in life. Studies have demonstrated an increased risk of prostate cancer in men with symptomatic prostatitis (Dennis et al. 2002, Roberts et al. 2004). This includes risk from bacterial and other infections (Cheng et al. 2010). However, due to a lack of causative factors, the links have never been formally established, despite studies showing that inflammation is frequently present in prostate biopsies, radical prostatectomy specimens, and tissue resected for treatment of BPH (Platz & De Marzo 2004). Common anti-inflammatory drugs were found to lower the levels of serum prostate-specific antigen (PSA), a marker of prostate cancer progression (Chang et al. 2010). Although no relation between the use of antibiotics, aspirin, or NSAIDs and the risk of prostate cancer could be determined (Daniels et al. 2009), a Phase II trial of the potent anti-inflammatory drug celecoxib (a COX-2 inhibitor) suppressed PSA progression in patients who experienced biochemical progression following radical prostatectomy or radiation therapy (Pruthi et al. 2006). These studies further indicate a relationship between inflammation and prostate cancer.

Despite epidemiological evidence, until now, the mechanism linking these two events has been lacking. In recent times, various inflammatory cytokines have been found to mediate the proliferation of prostate cancer cells, such as IL6 (Dutt & Gao 2009) and the macrophage inhibitory cytokine (MIC1; GDF15) gene (Dubey et al. 2012). Another important regulator of prostate cancer progression now appears to be the macrophage migration inhibitory factor (MIF), also known as glycosylation-inhibiting factor, a pro-inflammatory cytokine and an important regulator of innate immunity (Nishihira et al. 2003). MIF is released into circulation following infection, glucocorticoid release, or trauma. This cytokine has been implicated in the development and progression of multiple types of tumors. Significantly, this cytokine appears to have a biphasic response: MIF produced by stromal cells but not by tumor cells regulates angiogenesis in various cancers (Verjans et al. 2009, Girard et al. 2012).

The role of MIF in prostate cancer development and progression is not unknown. As early as 1996, investigators have shown that this gene may regulate prostate cancer metastasis (Meyer-Siegler & Hudson 1996). Another early study has shown neuroendocrine differentiation (NED) and MIF expression by the COX-2 inhibitor NS-398 (Meyer-Siegler 2001). The effect of MIF in the cell is mediated by its receptor CD74 (Meyer-Siegler et al. 2006); however, the mechanism by which this cytokine plays a role in prostate cancer progression had not been elucidated.

This missing link has now been provided by Tawadros et al. (2013) in the February issue of Endocrine-Related Cancer. This group has for long been interested in the study of NED in prostate cancer (Tawadros et al. 2005) and has now shown that MIF activates proliferation and survival through the stimulation of Akt and ERK pathways. Neuroendocrine (NE) cells are a component of the normal prostate, and many of the factors shown to be produced by NE cells are known to support growth and differentiation in the prostate (Nelson et al. 2007). Both benign prostate and malignant prostate depend upon the androgen receptor (AR) for growth and survival; hence, androgen deprivation therapy is a cornerstone of treatment for advanced, especially metastatic, prostate cancer (Ruizeveld de Winter et al. 1994, Culig et al. 2000). The expression of the AR in NE tumors is slightly different. Benign and malignant prostatic tissues contain both AR-positive and AR-negative NE cells (Nakada et al. 1993); however, a prevalence of AR-negative NE cells has been reported in more advanced disease (Krijnen et al. 1993, Bonkhoff 1998). NE cells in prostate cancer appear to be distinct from NE cells in benign prostate and may result from the transdifferentiation of epithelial cells (Nelson et al. 2007). Several varieties of prostatic NED have been described, including highly malignant NE cells of the small-cell carcinoma and carcinoid tumors. In prostatic adenocarcinoma, individual NE cells are surrounded by small foci of epithelial cells (Nelson et al. 2007). In general, NE differentiation is accompanied by a worse prognosis and resistance to therapy (Fixemer et al. 2002). The NE differentiation marker chromogranin A (CgA) is considered to be a marker of advanced disease (Berruti et al. 2010), although the value of NE markers in predicting disease progression is not uniformly accepted (Jeetle et al. 2012).

Various inflammatory cytokines have been reported to induce NED in prostate cancer cells (Kim et al. 2004), and in turn, NED has been shown to cause the release of various cytokines that stimulated prostate cancer progression (Nelson et al. 2007). Earlier studies have shown that the COX-2 inhibitor NS-398 increased MIF production and stimulated NED in prostate cancer cells (Meyer-Siegler 2001). However, the link between NED and MIF secretion had not been established. Now, Tawadros et al. (2013), using androgen-dependent LNCaP prostate cancer cells as a model, show that NED caused by either cAMP treatment or androgen deprivation, a standard therapy for prostate cancer, results in an increase in extracellular MIF secretion but a decrease in intracellular MIF protein and transcription levels. Significantly, extracellular MIF increase did not affect PSA levels, but yet resulted in increased proliferation. Since PSA expression is known to be AR regulated, this result indicates that the tumor-enhancing effects of MIF are AR independent. This result is important, since LNCaP cells express an active AR and support the growing body of literature stating that PSA levels do not accurately reflect tumor progression. MIF is known to activate both Akt and ERK signaling pathways (Ohta et al. 2012), and in prostate cancer cell lines, these pathways have been found to mediate proliferation. These pathways can be activated by both AR-dependent and AR-independent mechanisms, and in this case, these are clearly AR independent. Since both pathways have also been shown to stimulate AR transcriptional activity in prostate cancer cells, it is curious as to why they did not affect PSA expression in this case. It is likely that the AR is completely bypassed in NED, such that not only does it not affect proliferation, but it also does not get transactivated by common pathways. In short, Tawadros et al. demonstrate that the paracrine action of MIF, but not autocrine action, induced NED differentiation and stimulated cell proliferation mediated by both ERK and Akt phosphorylation.

The significance of this paper lies in its ability to link MIF release in chronic inflammation, as seen, for example, in prostatitis and other prostate diseases caused by infections, to the development of NED in prostate cancer cells. MIF action is mediated by the cytokine receptor CD74, which plays a role in antigen presentation (Beswick & Reyes 2009). MIF has been implicated in lethal bacterial sepsis and the mediation of effects of endotoxins released by Gram-negative bacteria (Calandra & Roger 2003). With the advent of studies showing a positive correlation between infections and prostate cancer (Taylor et al. 2005, Cheng et al. 2010), the role of MIF in prostate cancer is likely to increase in importance. The number of MIF inhibitors available today is clearly inadequate (Ouertatani-Sakouhi et al. 2010, Fujita et al. 2012), but novel MIF inhibitors are being developed (Garai & Lorand 2009, Lugrin et al. 2009, Ouertatani-Sakouhi et al. 2009, Piette et al. 2009) and may in the future have a use in the chemoprevention of prostate cancer in men with prostatitis.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

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    • Search Google Scholar
    • Export Citation
  • Beswick EJ & Reyes VE 2009 CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract. World Journal of Gastroenterology 15 28552861. (doi:10.3748/wjg.15.2855).

    • Search Google Scholar
    • Export Citation
  • Bonkhoff H 1998 Neuroendocrine cells in benign and malignant prostate tissue: morphogenesis, proliferation, and androgen receptor status. Prostate. Supplement 8 1822. (doi:10.1002/(SICI)1097-0045(1998)8+<18::AID-PROS4>3.0.CO;2-C).

    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
  • Chang SL, Harshman LC & Presti JC Jr 2010 Impact of common medications on serum total prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. Journal of Clinical Oncology 28 39513957. (doi:10.1200/JCO.2009.27.9406).

    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
  • Daniels NA, Chen YH & Bent S 2009 Antibiotic and anti-inflammatory use and the risk of prostate cancer. BMC Research Notes 2 57. (doi:10.1186/1756-0500-2-57).

    • Search Google Scholar
    • Export Citation
  • Dennis LK, Lynch CF & Torner JC 2002 Epidemiologic association between prostatitis and prostate cancer. Urology 60 7883. (doi:10.1016/S0090-4295(02)01637-0).

    • Search Google Scholar
    • Export Citation
  • Dubey S, Vanveldhuizen P, Holzbeierlein J, Tawfik O, Thrasher JB & Karan D 2012 Inflammation-associated regulation of the macrophage inhibitory cytokine (MIC-1) gene in prostate cancer. Oncology Letters 3 11661170.

    • Search Google Scholar
    • Export Citation
  • Dutt SS & Gao AC 2009 Molecular mechanisms of castration-resistant prostate cancer progression. Future Oncology 5 14031413. (doi:10.2217/fon.09.117).

    • Search Google Scholar
    • Export Citation
  • Fixemer T, Remberger K & Bonkhoff H 2002 Apoptosis resistance of neuroendocrine phenotypes in prostatic adenocarcinoma. Prostate 53 118123. (doi:10.1002/pros.10133).

    • Search Google Scholar
    • Export Citation
  • Fujita Y, Islam R, Sakai K, Kaneda H, Kudo K, Tamura D, Aomatsu K, Nagai T, Kimura H & Matsumoto K et al. 2012 Aza-derivatives of resveratrol are potent macrophage migration inhibitory factor inhibitors. Investigational New Drugs 30 18781886. (doi:10.1007/s10637-011-9749-7).

    • Search Google Scholar
    • Export Citation
  • Garai J & Lorand T 2009 Macrophage migration inhibitory factor (MIF) tautomerase inhibitors as potential novel anti-inflammatory agents: current developments. Current Medicinal Chemistry 16 10911114. (doi:10.2174/092986709787581842).

    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
  • Lugrin J, Ding XC, Le Roy D, Chanson AL, Sweep FC, Calandra T & Roger T 2009 Histone deacetylase inhibitors repress macrophage migration inhibitory factor (MIF) expression by targeting MIF gene transcription through a local chromatin deacetylation. Biochimica et Biophysica Acta 1793 17491758. (doi:10.1016/j.bbamcr.2009.09.007).

    • Search Google Scholar
    • Export Citation
  • Meyer-Siegler K 2001 COX-2 specific inhibitor, NS-398, increases macrophage migration inhibitory factor expression and induces neuroendocrine differentiation in C4-2b prostate cancer cells. Molecular Medicine 7 850860.

    • Search Google Scholar
    • Export Citation
  • Meyer-Siegler K & Hudson PB 1996 Enhanced expression of macrophage migration inhibitory factor in prostatic adenocarcinoma metastases. Urology 48 448452. (doi:10.1016/S0090-4295(96)00207-5).

    • Search Google Scholar
    • Export Citation
  • Meyer-Siegler KL, Iczkowski KA, Leng L, Bucala R & Vera PL 2006 Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells. Journal of Immunology 177 87308739.

    • Search Google Scholar
    • Export Citation
  • Nakada SY, di Sant'Agnese PA, Moynes RA, Hiipakka RA, Liao S, Cockett AT & Abrahamsson PA 1993 The androgen receptor status of neuroendocrine cells in human benign and malignant prostatic tissue. Cancer Research 53 19671970.

    • Search Google Scholar
    • Export Citation
  • Nelson EC, Cambio AJ, Yang JC, Ok JH, Lara PN Jr & Evans CP 2007 Clinical implications of neuroendocrine differentiation in prostate cancer. Prostate Cancer and Prostatic Diseases 10 614. (doi:10.1038/sj.pcan.4500922).

    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
  • Platz EA & De Marzo AM 2004 Epidemiology of inflammation and prostate cancer. Journal of Urology 171 S36S40. (doi:10.1097/01.ju.0000108131.43160.77).

    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
  • Tawadros T, Martin D, Abderrahmani A, Leisinger HJ, Waeber G & Haefliger JA 2005 IB1/JIP-1 controls JNK activation and increased during prostatic LNCaP cells neuroendocrine differentiation. Cellular Signalling 17 929939. (doi:10.1016/j.cellsig.2004.11.013).

    • Search Google Scholar
    • Export Citation
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  • Berruti A, Bollito E, Cracco CM, Volante M, Ciccone G, Porpiglia F, Papotti M, Scarpa RM & Dogliotti L 2010 The prognostic role of immunohistochemical chromogranin a expression in prostate cancer patients is significantly modified by androgen-deprivation therapy. Prostate 70 718726. (doi:10.1002/pros.21104).

    • Search Google Scholar
    • Export Citation
  • Beswick EJ & Reyes VE 2009 CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract. World Journal of Gastroenterology 15 28552861. (doi:10.3748/wjg.15.2855).

    • Search Google Scholar
    • Export Citation
  • Bonkhoff H 1998 Neuroendocrine cells in benign and malignant prostate tissue: morphogenesis, proliferation, and androgen receptor status. Prostate. Supplement 8 1822. (doi:10.1002/(SICI)1097-0045(1998)8+<18::AID-PROS4>3.0.CO;2-C).

    • Search Google Scholar
    • Export Citation
  • Calandra T & Roger T 2003 Macrophage migration inhibitory factor: a regulator of innate immunity. Nature Reviews. Immunology 3 791800. (doi:10.1038/nri1200).

    • Search Google Scholar
    • Export Citation
  • Chang SL, Harshman LC & Presti JC Jr 2010 Impact of common medications on serum total prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. Journal of Clinical Oncology 28 39513957. (doi:10.1200/JCO.2009.27.9406).

    • Search Google Scholar
    • Export Citation
  • Cheng I, Witte JS, Jacobsen SJ, Haque R, Quinn VP, Quesenberry CP, Caan BJ & Van Den Eeden SK 2010 Prostatitis, sexually transmitted diseases, and prostate cancer: the California Men's Health Study. PLoS ONE 5 e8736. (doi:10.1371/journal.pone.0008736).

    • Search Google Scholar
    • Export Citation
  • Culig Z, Hobisch A, Bartsch G & Klocker H 2000 Androgen receptor – an update of mechanisms of action in prostate cancer. Urological Research 28 211219. (doi:10.1007/s002400000111).

    • Search Google Scholar
    • Export Citation
  • Daniels NA, Chen YH & Bent S 2009 Antibiotic and anti-inflammatory use and the risk of prostate cancer. BMC Research Notes 2 57. (doi:10.1186/1756-0500-2-57).

    • Search Google Scholar
    • Export Citation
  • Dennis LK, Lynch CF & Torner JC 2002 Epidemiologic association between prostatitis and prostate cancer. Urology 60 7883. (doi:10.1016/S0090-4295(02)01637-0).

    • Search Google Scholar
    • Export Citation
  • Dubey S, Vanveldhuizen P, Holzbeierlein J, Tawfik O, Thrasher JB & Karan D 2012 Inflammation-associated regulation of the macrophage inhibitory cytokine (MIC-1) gene in prostate cancer. Oncology Letters 3 11661170.

    • Search Google Scholar
    • Export Citation
  • Dutt SS & Gao AC 2009 Molecular mechanisms of castration-resistant prostate cancer progression. Future Oncology 5 14031413. (doi:10.2217/fon.09.117).

    • Search Google Scholar
    • Export Citation
  • Fixemer T, Remberger K & Bonkhoff H 2002 Apoptosis resistance of neuroendocrine phenotypes in prostatic adenocarcinoma. Prostate 53 118123. (doi:10.1002/pros.10133).

    • Search Google Scholar
    • Export Citation
  • Fujita Y, Islam R, Sakai K, Kaneda H, Kudo K, Tamura D, Aomatsu K, Nagai T, Kimura H & Matsumoto K et al. 2012 Aza-derivatives of resveratrol are potent macrophage migration inhibitory factor inhibitors. Investigational New Drugs 30 18781886. (doi:10.1007/s10637-011-9749-7).

    • Search Google Scholar
    • Export Citation
  • Garai J & Lorand T 2009 Macrophage migration inhibitory factor (MIF) tautomerase inhibitors as potential novel anti-inflammatory agents: current developments. Current Medicinal Chemistry 16 10911114. (doi:10.2174/092986709787581842).

    • Search Google Scholar
    • Export Citation
  • Girard E, Strathdee C, Trueblood E & Queva C 2012 Macrophage migration inhibitory factor produced by the tumour stroma but not by tumour cells regulates angiogenesis in the B16-F10 melanoma model. British Journal of Cancer 107 14981505. (doi:10.1038/bjc.2012.392).

    • Search Google Scholar
    • Export Citation
  • Jeetle SS, Fisher G, Yang ZH, Stankiewicz E, Moller H, Cooper CS, Cuzick J, Berney DM & Trans-Atlantic Prostate G 2012 Neuroendocrine differentiation does not have independent prognostic value in conservatively treated prostate cancer. Virchows Archiv 461 103107. (doi:10.1007/s00428-012-1259-2).

    • Search Google Scholar
    • Export Citation
  • Kim J, Adam RM, Solomon KR & Freeman MR 2004 Involvement of cholesterol-rich lipid rafts in interleukin-6-induced neuroendocrine differentiation of LNCaP prostate cancer cells. Endocrinology 145 613619. (doi:10.1210/en.2003-0772).

    • Search Google Scholar
    • Export Citation
  • Krijnen JL, Janssen PJ, Ruizeveld de Winter JA, van Krimpen H, Schroder FH & van der Kwast TH 1993 Do neuroendocrine cells in human prostate cancer express androgen receptor? Histochemistry 100 393398. (doi:10.1007/BF00268938).

    • Search Google Scholar
    • Export Citation
  • Lugrin J, Ding XC, Le Roy D, Chanson AL, Sweep FC, Calandra T & Roger T 2009 Histone deacetylase inhibitors repress macrophage migration inhibitory factor (MIF) expression by targeting MIF gene transcription through a local chromatin deacetylation. Biochimica et Biophysica Acta 1793 17491758. (doi:10.1016/j.bbamcr.2009.09.007).

    • Search Google Scholar
    • Export Citation
  • Meyer-Siegler K 2001 COX-2 specific inhibitor, NS-398, increases macrophage migration inhibitory factor expression and induces neuroendocrine differentiation in C4-2b prostate cancer cells. Molecular Medicine 7 850860.

    • Search Google Scholar
    • Export Citation
  • Meyer-Siegler K & Hudson PB 1996 Enhanced expression of macrophage migration inhibitory factor in prostatic adenocarcinoma metastases. Urology 48 448452. (doi:10.1016/S0090-4295(96)00207-5).

    • Search Google Scholar
    • Export Citation
  • Meyer-Siegler KL, Iczkowski KA, Leng L, Bucala R & Vera PL 2006 Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells. Journal of Immunology 177 87308739.

    • Search Google Scholar
    • Export Citation
  • Nakada SY, di Sant'Agnese PA, Moynes RA, Hiipakka RA, Liao S, Cockett AT & Abrahamsson PA 1993 The androgen receptor status of neuroendocrine cells in human benign and malignant prostatic tissue. Cancer Research 53 19671970.

    • Search Google Scholar
    • Export Citation
  • Nelson EC, Cambio AJ, Yang JC, Ok JH, Lara PN Jr & Evans CP 2007 Clinical implications of neuroendocrine differentiation in prostate cancer. Prostate Cancer and Prostatic Diseases 10 614. (doi:10.1038/sj.pcan.4500922).

    • Search Google Scholar
    • Export Citation
  • 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. Annals of the New York Academy of Sciences 995 171182. (doi:10.1111/j.1749-6632.2003.tb03220.x).

    • Search Google Scholar
    • Export Citation
  • Ohta S, Misawa A, Fukaya R, Inoue S, Kanemura Y, Okano H, Kawakami Y & Toda M 2012 Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells. Journal of Cell Science 125 32103220. (doi:10.1242/jcs.102210).

    • Search Google Scholar
    • Export Citation
  • Ouertatani-Sakouhi H, El-Turk F, Fauvet B, Roger T, Le Roy D, Karpinar DP, Leng L, Bucala R, Zweckstetter M & Calandra T et al. 2009 A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor. Biochemistry 48 98589870. (doi:10.1021/bi900957e).

    • Search Google Scholar
    • Export Citation
  • Ouertatani-Sakouhi H, El-Turk F, Fauvet B, Cho MK, Pinar Karpinar D, Le Roy D, Dewor M, Roger T, Bernhagen J & Calandra T et al. 2010 Identification and characterization of novel classes of macrophage migration inhibitory factor (MIF) inhibitors with distinct mechanisms of action. Journal of Biological Chemistry 285 2658126598. (doi:10.1074/jbc.M110.113951).

    • Search Google Scholar
    • Export Citation
  • Piette C, Deprez M, Roger T, Noel A, Foidart JM & Munaut C 2009 The dexamethasone-induced inhibition of proliferation, migration, and invasion in glioma cell lines is antagonized by macrophage migration inhibitory factor (MIF) and can be enhanced by specific MIF inhibitors. Journal of Biological Chemistry 284 3248332492. (doi:10.1074/jbc.M109.014589).

    • Search Google Scholar
    • Export Citation
  • Platz EA & De Marzo AM 2004 Epidemiology of inflammation and prostate cancer. Journal of Urology 171 S36S40. (doi:10.1097/01.ju.0000108131.43160.77).

    • Search Google Scholar
    • Export Citation
  • Pruthi RS, Derksen JE, Moore D, Carson CC, Grigson G, Watkins C & Wallen E 2006 Phase II trial of celecoxib in prostate-specific antigen recurrent prostate cancer after definitive radiation therapy or radical prostatectomy. Clinical Cancer Research 12 21722177. (doi:10.1158/1078-0432.CCR-05-2067).

    • Search Google Scholar
    • Export Citation
  • Roberts RO, Bergstralh EJ, Bass SE, Lieber MM & Jacobsen SJ 2004 Prostatitis as a risk factor for prostate cancer. Epidemiology 15 9399. (doi:10.1097/01.ede.0000101022.38330.7c).

    • Search Google Scholar
    • Export Citation
  • Ruizeveld de Winter JA, Janssen PJ, Sleddens HM, Verleun-Mooijman MC, Trapman J, Brinkmann AO, Santerse AB, Schroder FH & van der Kwast TH 1994 Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. American Journal of Pathology 144 735746.

    • Search Google Scholar
    • Export Citation
  • Tawadros T, Martin D, Abderrahmani A, Leisinger HJ, Waeber G & Haefliger JA 2005 IB1/JIP-1 controls JNK activation and increased during prostatic LNCaP cells neuroendocrine differentiation. Cellular Signalling 17 929939. (doi:10.1016/j.cellsig.2004.11.013).

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