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Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway

Oncogene volume 29, pages 1167–1178 (2010)Cite this article

Abstract

Ras signaling pathways are well-recognized for their involvement in cancer cell proliferation; however, considerably less is known regarding their contribution to invasion and metastasis. Here, we demonstrate that a novel BLT2, a low-affinity leukotriene B4 receptor-linked signaling cascade involving the generation of reactive oxygen species (ROS) via Nox1, NF-κB stimulation and subsequent upregulation of matrix metalloproteinase-9 (MMP-9) is a potential mechanism by which Ras promotes invasion and metastasis. We found that inhibition of BLT2 signaling markedly suppressed Ras-evoked metastasis and reduced the associated mortality in mice. Consistent with the proposed role of BLT2 as a key downstream mediator of Ras signaling to metastasis, BLT2 expression alone resulted in the formation of numerous metastatic lung nodules and the nodules formation was significantly attenuated by the inhibition of MMP-9, a downstream component of BLT2. Together, our results reveal the previously unsuspected function of BLT2-linked cascade in driving oncogenic Ras-induced metastasis and would provide a valuable insight into invasion and metastasis.

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References

  • Behrend L, Henderson G, Zwacka RM . (2003). Reactive oxygen species in oncogenic transformation. Biochem Soc Trans 31: 1441–1444.

    Article  CAS  PubMed  Google Scholar 

  • Bjorklund M, Koivunen E . (2005). Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta 1755: 37–69.

    PubMed  Google Scholar 

  • Bondy GP, Wilson S, Chambers AF . (1985). Experimental metastatic ability of H-ras-transformed NIH3T3 cells. Cancer Res 45: 6005–6009.

    CAS  PubMed  Google Scholar 

  • Bonfil RD, Sabbota A, Nabha S, Bernardo MM, Dong Z, Meng H et al. (2006). Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism-based selective gelatinase inhibitor. Int J Cancer 118: 2721–2726.

    Article  CAS  PubMed  Google Scholar 

  • Bortuzzo C, Hanif R, Kashfi K, Staiano-Coico L, Shiff SJ, Rigas B . (1996). The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells. Biochim Biophys Acta 1300: 240–246.

    Article  PubMed  Google Scholar 

  • Bos JL . (1989). ras oncogenes in human cancer: a review. Cancer Res 49: 4682–4689.

    CAS  PubMed  Google Scholar 

  • Brock TG, Peters-Golden M . (2007). Activation and regulation of cellular eicosanoid biosynthesis. ScientificWorldJournal 7: 1273–1284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell PM, Der CJ . (2004). Oncogenic Ras and its role in tumor cell invasion and metastasis. Semin Cancer Biol 14: 105–114.

    Article  CAS  PubMed  Google Scholar 

  • Cha YI, DuBois RN . (2007). NSAIDs and cancer prevention: targets downstream of COX-2. Annu Rev Med 58: 239–252.

    Article  CAS  PubMed  Google Scholar 

  • Choi JA, Kim EY, Song H, Kim C, Kim JH . (2008). Reactive oxygen species are generated through a BLT2-linked cascade in Ras-transformed cells. Free Radic Biol Med 44: 624–634.

    Article  CAS  PubMed  Google Scholar 

  • Choi JA, Lee JW, Kim H, Kim EY, Seo JM, Ko JS et al. (2009). Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway. Carcinogenesis, doi:10.1093/carcin/bgp203.

    Article  PubMed  Google Scholar 

  • Chun KS, Surh YJ . (2004). Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. Biochem Pharmacol 68: 1089–1100.

    Article  CAS  PubMed  Google Scholar 

  • Deryugina EI, Quigley JP . (2006). Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25: 9–34.

    Article  CAS  PubMed  Google Scholar 

  • Ding XZ, Hennig R, Adrian TE . (2003). Lipoxygenase and cyclooxygenase metabolism: new insights in treatment and chemoprevention of pancreatic cancer. Mol Cancer 2: 10.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ding XZ, Talamonti MS, Bell Jr RH, Adrian TE . (2005). A novel anti-pancreatic cancer agent, LY293111. Anticancer Drugs 16: 467–473.

    Article  CAS  PubMed  Google Scholar 

  • Downward J . (2003). Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3: 11–22.

    Article  CAS  PubMed  Google Scholar 

  • Giehl K . (2005). Oncogenic Ras in tumour progression and metastasis. Biol Chem 386: 193–205.

    CAS  PubMed  Google Scholar 

  • Gu Z, Cui J, Brown S, Fridman R, Mobashery S, Strongin AY et al. (2005). A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci 25: 6401–6408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harris RE . (2007). Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. Subcell Biochem 42: 93–126.

    Article  PubMed  Google Scholar 

  • Hennig R, Osman T, Esposito I, Giese N, Rao SM, Ding XZ et al. (2008). BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation. Br J Cancer 99: 1064–1073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hennig R, Ventura J, Segersvard R, Ward E, Ding XZ, Rao SM et al. (2005). LY293111 improves efficacy of gemcitabine therapy on pancreatic cancer in a fluorescent orthotopic model in athymic mice. Neoplasia 7: 417–425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heukamp I, Kilian M, Gregor JI, Kiewert C, Schimke I, Kristiansen G et al. (2006). Impact of polyunsaturated fatty acids on hepato-pancreatic prostaglandin and leukotriene concentration in ductal pancreatic cancer -- is there a correlation to tumour growth and liver metastasis? Prostaglandins Leukot Essent Fatty Acids 74: 223–233.

    Article  CAS  PubMed  Google Scholar 

  • Hsu TC, Young MR, Cmarik J, Colburn NH . (2000). Activator protein 1 (AP-1)- and nuclear factor kappaB (NF-kappaB)-dependent transcriptional events in carcinogenesis. Free Radic Biol Med 28: 1338–1348.

    Article  CAS  PubMed  Google Scholar 

  • Iizuka Y, Yokomizo T, Terawaki K, Komine M, Tamaki K, Shimizu T . (2005). Characterization of a mouse second leukotriene B4 receptor, mBLT2: BLT2-dependent ERK activation and cell migration of primary mouse keratinocytes. J Biol Chem 280: 24816–24823.

    Article  CAS  PubMed  Google Scholar 

  • Kim GY, Lee JW, Cho SH, Seo JM, Kim JH . (2009). Role of the low-affinity leukotriene B4 receptor BLT2 in VEGF-induced angiogenesis. Arterioscler Thromb Vasc Biol 6: 915–920.

    Article  Google Scholar 

  • Kruger A, Arlt MJ, Gerg M, Kopitz C, Bernardo MM, Chang M et al. (2005). Antimetastatic activity of a novel mechanism-based gelatinase inhibitor. Cancer Res 65: 3523–3526.

    Article  PubMed  Google Scholar 

  • Kumar CC, Bushel P, Mohan-Peterson S, Ramirez F . (1992). Regulation of smooth muscle alpha-actin promoter in ras-transformed cells: usefulness for setting up reporter gene-based assay system for drug screening. Cancer Res 52: 6877–6884.

    CAS  PubMed  Google Scholar 

  • Lee KW, Kim MS, Kang NJ, Kim DH, Surh YJ, Lee HJ et al. (2006). H-Ras selectively up-regulates MMP-9 and COX-2 through activation of ERK1/2 and NF-kappaB: an implication for invasive phenotype in rat liver epithelial cells. Int J Cancer 119: 1767–1775.

    Article  CAS  PubMed  Google Scholar 

  • Mayoral R, Fernandez-Martinez A, Bosca L, Martin-Sanz P . (2005). Prostaglandin E2 promotes migration and adhesion in hepatocellular carcinoma cells. Carcinogenesis 26: 753–761.

    Article  CAS  PubMed  Google Scholar 

  • Nie D, Che M, Grignon D, Tang K, Honn KV . (2001). Role of eicosanoids in prostate cancer progression. Cancer Metastasis Rev 20: 195–206.

    Article  CAS  PubMed  Google Scholar 

  • Nikkola J, Vihinen P, Vuoristo MS, Kellokumpu-Lehtinen P, Kahari VM, Pyrhonen S . (2005). High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res 11: 5158–5166.

    Article  CAS  PubMed  Google Scholar 

  • Oft M, Akhurst RJ, Balmain A . (2002). Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol 4: 487–494.

    Article  CAS  PubMed  Google Scholar 

  • Qiu H, Johansson AS, Sjostrom M, Wan M, Schroder O, Palmblad J et al. (2006). Differential induction of BLT receptor expression on human endothelial cells by lipopolysaccharide, cytokines, and leukotriene B4. Proc Natl Acad Sci USA 103: 6913–6918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rocconi RP, Kirby TO, Seitz RS, Beck R, Straughn Jr JM, Alvarez RD et al. (2008). Lipoxygenase pathway receptor expression in ovarian cancer. Reprod Sci 15: 321–326.

    Article  PubMed  Google Scholar 

  • Romano M, Claria J . (2003). Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB J 17: 1986–1995.

    Article  CAS  PubMed  Google Scholar 

  • Shin EH, Lee HY, Bae YS . (2006). Leukotriene B4 stimulates human monocyte-derived dendritic cell chemotaxis. Biochem Biophys Res Commun 348: 606–611.

    Article  CAS  PubMed  Google Scholar 

  • Su ZZ, Austin VN, Zimmer SG, Fisher PB . (1993). Defining the critical gene expression changes associated with expression and suppression of the tumorigenic and metastatic phenotype in Ha-ras-transformed cloned rat embryo fibroblast cells. Oncogene 8: 1211–1219.

    CAS  PubMed  Google Scholar 

  • Subbaramaiah K, Norton L, Gerald W, Dannenberg AJ . (2002). Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. J Biol Chem 277: 18649–18657.

    Article  CAS  PubMed  Google Scholar 

  • Tong WG, Ding XZ, Hennig R, Witt RC, Standop J, Pour PM et al. (2002). Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Clin Cancer Res 8: 3232–3242.

    CAS  PubMed  Google Scholar 

  • Van Putten V, Refaat Z, Dessev C, Blaine S, Wick M, Butterfield L et al. (2001). Induction of cytosolic phospholipase A2 by oncogenic Ras is mediated through the JNK and ERK pathways in rat epithelial cells. J Biol Chem 276: 1226–1232.

    Article  CAS  PubMed  Google Scholar 

  • Wang MT, Honn KV, Nie D . (2007). Cyclooxygenases, prostanoids, and tumor progression. Cancer Metastasis Rev 26: 525–534.

    Article  CAS  PubMed  Google Scholar 

  • Woo CH, You HJ, Cho SH, Eom YW, Chun JS, Yoo YJ et al. (2002). Leukotriene B(4) stimulates Rac-ERK cascade to generate reactive oxygen species that mediates chemotaxis. J Biol Chem 277: 8572–8578.

    Article  CAS  PubMed  Google Scholar 

  • Wu WS . (2006). The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev 25: 695–705.

    Article  CAS  PubMed  Google Scholar 

  • Yang JQ, Zhao W, Duan H, Robbins ME, Buettner GR, Oberley LW et al. (2001). v-Ha-RaS oncogene upregulates the 92-kDa type IV collagenase (MMP-9) gene by increasing cellular superoxide production and activating NF-kappaB. Free Radic Biol Med 31: 520–529.

    Article  CAS  PubMed  Google Scholar 

  • Yokomizo T, Kato K, Hagiya H, Izumi T, Shimizu T . (2001). Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2. J Biol Chem 276: 12454–12459.

    Article  CAS  PubMed  Google Scholar 

  • Yokomizo T, Kato K, Terawaki K, Izumi T, Shimizu T . (2000). A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J Exp Med 192: 421–432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yokomizo T, Uozumi N, Takahashi T, Kume K, Izumi T, Shimizu T . (1995). Leukotriene A4 hydrolase and leukotriene B4 metabolism. J Lipid Mediat Cell Signal 12: 321–332.

    Article  CAS  PubMed  Google Scholar 

  • Yoo MH, Song H, Woo CH, Kim H, Kim JH . (2004). Role of the BLT2, a leukotriene B4 receptor, in Ras transformation. Oncogene 23: 9259–9268.

    Article  CAS  PubMed  Google Scholar 

  • Yoo MH, Woo CH, You HJ, Cho SH, Kim BC, Choi JE et al. (2001). Role of the cytosolic phospholipase A2-linked cascade in signaling by an oncogenic, constitutively active Ha-Ras isoform. J Biol Chem 276: 24645–24653.

    Article  CAS  PubMed  Google Scholar 

  • Zampetaki A, Zhang Z, Hu Y, Xu Q . (2005). Biomechanical stress induces IL-6 expression in smooth muscle cells via Ras/Rac1-p38 MAPK-NF-kappaB signaling pathways. Am J Physiol Heart Circ Physiol 288: H2946–H2954.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Takao Shimizu (University of Tokyo, Tokyo, Japan) and Dr Takehiko Yokomizo (University of Kyushu, Fukuoka, Japan) for the BLT2 expression plasmids. This work was supported by the Diseases Network Research Program (M10751050001-08N5105-00110), and the SRC-Aging and Apoptosis Research program (20090062880) from the Ministry of Education, Science, and Technology, Korea.

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  1. Inflammatory Signaling Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea

    E-Y Kim, J-M Seo, K-J Cho & J-H Kim

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Correspondence to J-H Kim.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Kim, EY., Seo, JM., Cho, KJ. et al. Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway. Oncogene 29, 1167–1178 (2010). https://doi.org/10.1038/onc.2009.412

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