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HIF-1 and NF-κB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells

Oncogene volume 26, pages 7333–7345 (2007)Cite this article

Abstract

Hypoxic cancer cells are resistant to treatment, leading to the selection of cells with a more malignant phenotype. The expression of interleukin-8 (IL-8) plays an important role in the tumorigenesis and metastasis of solid tumors including prostate cancer. Recently, we detected elevated expression of IL-8 and IL-8 receptors in human prostate cancer tissue. The objective of the current study was to determine whether hypoxia increases IL-8 and IL-8 receptor expression in prostate cancer cells and whether this contributes to a survival advantage in hypoxic cells. IL-8, CXCR1 and CXCR2 messenger RNA (mRNA) expression in PC3 cells was upregulated in response to hypoxia in a time-dependent manner. Elevated IL-8 secretion following hypoxia was detected by enzyme-linked immunosorbent assay, while immunoblotting confirmed elevated receptor expression. Attenuation of hypoxia-inducible factor (HIF-1) and nuclear factor-κB (NF-κB) transcriptional activity using small interfering RNA (siRNA), a HIF-1 dominant-negative and pharmacological inhibitors, abrogated hypoxia-induced transcription of CXCR1 and CXCR2 in PC3 cells. Furthermore, chromatin-IP analysis demonstrated binding of HIF-1 and NF-κB to CXCR1. Finally, inhibition of IL-8 signaling potentiated etoposide-induced cell death in hypoxic PC3 cells. These results suggest that IL-8 signaling confers a survival advantage to hypoxic prostate cancer cells, and therefore, strategies to inhibit IL-8 signaling may sensitize hypoxic tumor cells to conventional treatments.

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References

  • Boland MP, Foster SJ, O’Neill LA . (1997). Daunorubicin activates NFkappaB and induces kappaB-dependent gene expression in HL-60 promyelocytic and Jurkat T-lymphoma cells. J Biol Chem 272: 12952–12960.

    Article  CAS  Google Scholar 

  • Brown LM, Cowen RL, Debray C, Eustace A, Erler JT, Sheppard FC et al. (2005). Reversing hypoxic cell chemoresistance in vitro using genetic and small molecule approaches targeting hypoxia inducible factor-1. Mol Pharmacol 69: 411–418.

    Article  Google Scholar 

  • Cairns RA, Hill RP . (2004). Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res 64: 2054–2061.

    Article  CAS  Google Scholar 

  • Cairns RA, Khokha R, Hill RP . (2003). Molecular mechanisms of tumor invasion and metastasis: an integrated view. Curr Mol Med 3: 659–671.

    Article  CAS  Google Scholar 

  • Carnell DM, Smith RE, Daley FM, Saunders MI, Bentzen SM, Hoskin PJ . (2006). An immunohistochemical assessment of hypoxia in prostate carcinoma using pimonidazole: implications for radioresistance. Int J Radiat Oncol Biol Phys 65: 91–99.

    Article  CAS  Google Scholar 

  • Coffey RNT, Morrissey C, Taylor CT, Fitzpatrick JM, Watson WG . (2005). Resistance to caspase-dependent, hypoxia-induced apoptosis is not hypoxia-inducible factor-1 alpha mediated in prostate carcinoma cells. Cancer 103: 1363–1374.

    Article  CAS  Google Scholar 

  • Cvetkovic D, Movsas B, Dicker AP, Hanlon AL, Greenberg RE, Chapman JD et al. (2001). Increased hypoxia correlates with increased expression of the angiogenesis marker vascular endothelial growth factor in human prostate cancer. Urology 57: 821–825.

    Article  CAS  Google Scholar 

  • Desbaillets I, Diserens AC, Tribolet N, Hamou MF, Van Meir EG . (1997). Upregulation of interleukin 8 by oxygen-deprived cells in glioblastoma suggests a role in leukocyte activation, chemotaxis, and angiogenesis. J Exp Med 186: 1201–1212.

    Article  CAS  Google Scholar 

  • Fernandez A, Udagawa T, Schwesinger C, Beecken W, Achilles-Gerte E, McDonnell T et al. (2001). Angiogenic potential of prostate carcinoma cells overexpressing bcl-2. J Natl Cancer Inst 93: 208–213.

    Article  CAS  Google Scholar 

  • Ghafar MA, Anastasiadis AG, Chen MW, Burchardt M, Olsson LE, Xie H et al. (2003). Acute hypoxia increases the aggressive characteristics and survival properties of prostate cancer cells. Prostate 54: 58–67.

    Article  Google Scholar 

  • Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ, Giaccia AJ . (1994). Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol 14: 6264–6277.

    Article  CAS  Google Scholar 

  • Grutkoski PS, Graeber CT, D'Amico R, Keeping H, Simms HH . (1999). Regulation of IL-8RA (CXCR1) expression in polymorphonuclear leukocytes by hypoxia/reoxygenation. J Leukoc Biol 65: 171–178.

    Article  CAS  Google Scholar 

  • Heidemann J, Ogawa H, Dwinell MB, Rafiee P, Maaser C, Gockel H et al. (2003). Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem 278: 8508–8515.

    Article  CAS  Google Scholar 

  • Hirota K, Semenza GL . (2006). Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol 59: 15–26.

    Article  Google Scholar 

  • Inoue K, Slaton JW, Eve BY, Kim SJ, Perrotte P, Balbay MD et al. (2000a). Interleukin-8 expression regulates tumorigenicity and metastasis in androgen-independent prostate cancer. Clin Cancer Res 6: 2104–2119.

    CAS  PubMed  Google Scholar 

  • Inoue K, Slaton JW, Kim SJ, Perrotte P, Eve BY, Bar-Eli M et al. (2000b). Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder cancer. Cancer Res 60: 2290–2299.

    CAS  PubMed  Google Scholar 

  • Kim KS, Rajagopal V, Gonsalves C, Johnson C, Kalra VK . (2006). A novel role of hypoxia-inducible factor in cobalt chloride- and hypoxia-mediated expression of IL-8 chemokine in human endothelial cells. J Immunol 177: 7211–7224.

    Article  CAS  Google Scholar 

  • Koong AC, Chen EY, Giaccia AJ . (1994). Hypoxia causes the activation of nuclear factor kappa B though the phosphorylation of I kappa B alpha on tyrosine residues. Cancer Res 54: 1425–1430.

    CAS  PubMed  Google Scholar 

  • Kunz M, Hartmann A, Flory E, Toksoy A, Koczan D, Thiesen HJ et al. (1999). Anoxia-induced up-regulation of interleukin-8 in human malignant melanoma. A potential mechanism for high tumor aggressiveness. Am J Pathol 155: 753–763.

    Article  CAS  Google Scholar 

  • Lee TH, Avraham H . (2002). Vascular endothelial growth factor modulates neutrophil transendothelial migration via up-regulation of interleukin-8 in human brain microvascular endothelial cells. J Biol Chem 277: 10445–10451.

    Article  CAS  Google Scholar 

  • Li A, Dubey S, Varney ML, Dave BJ, Singh RK . (2003). IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170: 3369–3376.

    Article  CAS  Google Scholar 

  • Li A, Varney ML, Valasek J, Godfrey M, Dave BJ, Singh RK . (2005). Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis 8: 63–71.

    Article  CAS  Google Scholar 

  • MacManus CF, Pettigrew J, Seaton A, Wilson C, Maxwell PJ, Berlingeri S et al. (2007). Interleukin-8 signaling promotes translational regulation of cyclin D in androgen-independent prostate cancer cells. Mol Cancer Res (in press).

  • Mizukami Y, Jo WS, Duerr EM, Gala M, Li J, Zhang X et al. (2005). Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 11: 992–997.

    Article  CAS  Google Scholar 

  • Moldobaeva A, Wagner EM . (2005). Difference in proangiogenic potential of systemic and pulmonary endothelium: role of CXCR2. Am J Physiol Lung Cell Mol Physiol 288: L1117–L1123.

    Article  CAS  Google Scholar 

  • Moore BB, Arenberg DA, Stoy K, Morgan T, Addison CL, Morris SB et al. (1999). Distinct CXC chemokines mediate tumorigenicity of prostate cancer cells. Am J Pathol 154: 1503–1512.

    Article  CAS  Google Scholar 

  • Mosmann T . (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Meth 65: 55–63.

    Article  CAS  Google Scholar 

  • Movsas B, Chapman JD, Horwitz EM, Pinover WH, Greenberg RE, Hanlon AL et al. (1999). Hypoxic regions exist in human prostate carcinoma. Urology 53: 11–18.

    Article  CAS  Google Scholar 

  • Murphy C, McGurk M, Pettigrew J, Santinelli A, Mazzucchelli R, Johnston PG et al. (2005). Nonapical and cytoplasmic expression of IL-8, CXCR1 and CXCR2 correlates with cell proliferation and microvessel density in prostate cancer. Clin Cancer Res 11: 4702–4711.

    Article  Google Scholar 

  • Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A et al. (2003). Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198: 1391–1402.

    Article  CAS  Google Scholar 

  • Semenza GL, Wang GL . (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythopoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12: 5447–5454.

    Article  CAS  Google Scholar 

  • Shi Q, Le X, Abbruzzese JL, Wang B, Mujaida N, Matsushima K et al. (1999). Cooperation between transcription factor AP-1 and NF-kappaB in the induction of interleukin-8 in human pancreatic adenocarcinoma cells by hypoxia. J Interferon Cytokine Res 19: 1363–1371.

    Article  CAS  Google Scholar 

  • Shi Q, Xiong Q, Le X, Xie K . (2001). Regulation of interleukin-8 expression by tumor associated stress factors. J Interferon Cytokine Res 21: 553–566.

    Article  CAS  Google Scholar 

  • Smith DR, Polverini PJ, Kunkel SL, Orringer MB, Whyte RI, Burdick MD et al. (1994). Inhibition of IL-8 attenuates angiogenesis in bronchogenic carcinoma. J Exp Med 179: 1409–1415.

    Article  CAS  Google Scholar 

  • Sowter HM, Raval RR, Moore JW, Ratcliffe PJ, Harris AL . (2003). Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res 63: 6130–6134.

    CAS  PubMed  Google Scholar 

  • Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W . (2003). Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumor suppressor pVHL. Nature 425: 307–311.

    Article  CAS  Google Scholar 

  • Subarsky P, Hill RP . (2003). The hypoxic tumor microenvironment and metastatic progression. Clin Exp Metastasis 20: 237–250.

    Article  CAS  Google Scholar 

  • Takaesu G, Surabhi RM, Park KJ, Ninomiya-Tsuji J, Matsumoto K, Gaynor RB . (2003). TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway. J Mol Biol 326: 105–115.

    Article  CAS  Google Scholar 

  • Takami M, Terry V, Petruzzelli L . (2002). Signaling pathways involved in IL-8-dependent activation of adhesion though Mac-1. J Immunol 168: 4559–4566.

    Article  CAS  Google Scholar 

  • Trisciuoglio D, Iervolino A, Zupi G, Del Bufalo D . (2005). Involvement of PI3K and MAPK signaling in bcl-2-induced vascular endothelial growth factor expression in melanoma cells. Mol Biol Cell 16: 4153–4162.

    Article  CAS  Google Scholar 

  • Vaupel P . (2004). The role of hypoxia-induced factors in tumor progression. Oncologist 9 (Suppl 4): 10–17.

    Article  CAS  Google Scholar 

  • Wingender E, Chen X, Hehl R, Karas H, Liebich I, Matys V et al. (2000). TRANSFAC: an integrated system for gene expression regulation. Nucleic Acids Res 28: 316–319.

    Article  CAS  Google Scholar 

  • Xu L, Pathak PS, Fukumura D . (2004). Hypoxia-induced activation of p38 mitogen-activated protein kinase and phosphatidylinositol-3-kinase signaling pathways contributes to expression of interleukin-8 in human ovarian carcinoma cells. Clin Cancer Res 10: 701–707.

    Article  CAS  Google Scholar 

  • Xu L, Xie K, Mukaida N, Matsushima K, Fidler IJ . (1999). Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells. Cancer Res 59: 5822–5829.

    CAS  PubMed  Google Scholar 

  • Yan SF, Lu J, Zou YS, Soh-Won J, Cohen DM, Buttrick PM et al. (1999). Hypoxia-associated induction of early growth response-1 gene expression. J Biol Chem 274: 15030–15040.

    Article  CAS  Google Scholar 

  • Yan SF, Zou YS, Mendelsohn M, Gao Y, Naka Y, Du Yan S et al. (1997). Nuclear factor interleukin 6 motifs mediate tissue-specific gene transcription in hypoxia. J Biol Chem 272: 4287–4294.

    Article  CAS  Google Scholar 

  • Yao KS, Xanthoudakis S, Curran T, O'Dwyer PJ . (1994). Activation of AP-1 and of a nuclear redox factor, Ref-1, in the response of HT29 colon cancer cells to hypoxia. Mol Cell Biol 14: 5997–6003.

    Article  CAS  Google Scholar 

  • Yasumoto K, Okamoto S, Mukaida N, Murakami S, Mai M, Matsushima K . (1992). Tumor necrosis factor alpha and interferon gamma synergistically induce interleukin 8 production in a human gastric cancer cell line though acting concurrently on AP-1 and NF-κB-like binding sites of the interleukin 8 gene. J Biol Chem 267: 22506–22511.

    CAS  PubMed  Google Scholar 

  • Yoneda J, Kuniyasu H, Crispens MA, Price JE, Bucana CD, Fidler IJ . (1998). Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice J. Natl Cancer Inst 90: 447–454.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by research grants from the Ulster Cancer Foundation (PGJ and DJJW), the Northern Ireland HPSS R&D Office (RRG9.14 to DJJW) and The Wellcome Trust (067104/Z/02/Z to DJJW).

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Authors and Affiliations

  1. Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, Northern Ireland

    P J Maxwell, R Gallagher, A Seaton, C Wilson, P Scullin, J Pettigrew, P G Johnston & D J J Waugh

  2. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK

    I J Stratford & K J Williams

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  1. P J Maxwell
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Correspondence to D J J Waugh.

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Maxwell, P., Gallagher, R., Seaton, A. et al. HIF-1 and NF-κB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells. Oncogene 26, 7333–7345 (2007). https://doi.org/10.1038/sj.onc.1210536

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