Inhibition of MAPK Kinase Signaling Pathways Suppressed Renal Cell Carcinoma Growth and Angiogenesis <i>In vivo</i>

Cancer Research - Tập 68 Số 1 - Trang 81-88 - 2008
Dan Huang1, Yan Ding2, Wang-Mei Luo1, Stephanie Bender1, Chao‐Nan Qian1,3, Eric J. Kort1, Zhongfa Zhang1, Kristin VandenBeldt4, Nicholas S. Duesbery2, James H. Resau4, Bin Tean Teh1,5
11Laboratory of Cancer Genetics,
22Laboratory of Cancer and Developmental Cell Biology, and
34Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China; and
43Laboratory of Analytical, Cellular, and Molecular Microscopy, Laboratory of Microarray Technology, Van Andel Research Institute, Grand Rapids, Michigan;
55NCCS-VARI Translational Research Laboratory, National Cancer Center, Singapore, Singapore

Tóm tắt

Abstract The mitogen-activated protein kinase (MAPK) signaling pathways play essential roles in cell proliferation and differentiation. Recent studies also show the activation of MAPK signaling pathways in tumorigenesis, metastasis, and angiogenesis of multiple human malignancies, including renal cell carcinoma (RCC). To assess the role of this pathway in regulating the proliferation and survival of RCC cells, we first examined the expression of MAPK kinase (MKK) and MAPK in clear cell RCC and confirmed the overexpression of MKK1 and extracellular signal-regulated kinase 2 (ERK2) in these tumors. We then tested the effects of pharmacologic inhibition of MKK on human RCC cell lines, both in vitro and in vivo, using anthrax lethal toxin (LeTx), which cleaves and inactivates several MKKs. Western blotting showed that the phosphorylation levels of ERK, c-Jun-NH2 kinase, and p38 MAPK decreased after 72 h of LeTx treatment. Exposure to LeTx for 72 h reduced cell proliferation by 20% without significant effects on cell cycle distribution and apoptosis. Anchorage-independent growth of RCC cells was dramatically inhibited by LeTx. In vivo studies showed that tumor growth of RCC xenografts could be suppressed by LeTx. Extensive necrosis and decreased tumor neovascularization were observed after LeTx treatment. LeTx also showed direct inhibition of proliferation of endothelial cells in vitro. Our results suggest that suppression of one or more MAPK signaling pathways may inhibit RCC growth through the disruption of tumor vasculature. [Cancer Res 2008;68(1):81–8]

Từ khóa


Tài liệu tham khảo

Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106–30.

Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996; 335: 865–75.

Goodman VL, Rock EP, Dagher R, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 2007; 13: 1367–73.

Rock EP, Goodman V, Jiang JX, et al. Food and Drug Administration drug approval summary: sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Oncologist 2007; 12: 107–13.

Kane RC, Farrell AT, Saber H, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 2006; 12: 7271–8.

Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature 2001; 410: 37–40.

Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298: 1911–2.

Dunn KL, Espino PS, Drobic B, He S, Davie JR. The Ras-MAPK signal transduction pathway, cancer and chromatin remodeling. Biochem Cell Biol 2005; 83: 1–14.

Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949–54.

Jeffers M, Fiscella M, Webb CP, Anver M, Koochekpour S, Vande Woude GF. The mutationally activated Met receptor mediates motility and metastasis. Proc Natl Acad Sci U S A 1998; 95: 14417–22.

Webb CP, Taylor GA, Jeffers M, et al. Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis. Oncogene 1998; 17: 2019–25.

Ward Y, Wang W, Woodhouse E, Linnoila I, Liotta L, Kelly K. Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways. Mol Cell Biol 2001; 21: 5958–69.

Sivaraman VS, Wang H, Nuovo GJ, Malbon CC. Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest 1997; 99: 1478–83.

Mandell JW, Hussaini IM, Zecevic M, Weber MJ, VandenBerg SR. In situ visualization of intratumor growth factor signaling: immunohistochemical localization of activated ERK/MAP kinase in glial neoplasms. Am J Pathol 1998; 153: 1411–23.

Hoshino R, Chatani Y, Yamori T, et al. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 1999; 18: 813–22.

Salh B, Marotta A, Matthewson C, et al. Investigation of the Mek-MAP kinase-Rsk pathway in human breast cancer. Anticancer Res 1999; 19: 731–40.

Giroux S, Tremblay M, Bernard D, et al. Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr Biol 1999; 9: 369–72.

Berra E, Milanini J, Richard DE, et al. Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. Biochem Pharmacol 2000; 60: 1171–8.

Dong G, Chen Z, Li ZY, Yeh NT, Bancroft CC, Van Waes C. Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Res 2001; 61: 5911–8.

Eliceiri BP, Klemke R, Stromblad S, Cheresh DA. Integrin αvβ3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis. J Cell Biol 1998; 140: 1255–63.

Depeille P, Young JJ, Boguslawski EA, et al. Anthrax lethal toxin inhibits growth of and vascular endothelial growth factor release from endothelial cells expressing the human herpes virus 8 viral g protein coupled receptor. Clin Cancer Res 2007; 13: 5926–34.

Oka H, Chatani Y, Hoshino R, et al. Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. Cancer Res 1995; 55: 4182–7.

Duesbery NS, Webb CP, Leppla SH, et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 1998; 280: 734–7.

Pellizzari R, Guidi-Rontani C, Vitale G, Mock M, Montecucco C. Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNγ-induced release of NO and TNFα. FEBS Lett 1999; 462: 199–204.

Vitale G, Pellizzari R, Recchi C, Napolitani G, Mock M, Montecucco C. Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages. Biochem Biophys Res Commun 1998; 248: 706–11.

Liang X, Young JJ, Boone SA, Waugh DS, Duesbery NS. Involvement of domain II in toxicity of anthrax lethal factor. J Biol Chem 2004; 279: 52473–8.

Duesbery NS, Resau J, Webb CP, et al. Suppression of ras-mediated transformation and inhibition of tumor growth and angiogenesis by anthrax lethal factor, a proteolytic inhibitor of multiple MEK pathways. Proc Natl Acad Sci U S A 2001; 98: 4089–94.

Koo HM, VanBrocklin M, McWilliams MJ, Leppla SH, Duesbery NS, Woude GF. Apoptosis and melanogenesis in human melanoma cells induced by anthrax lethal factor inactivation of mitogen-activated protein kinase kinase. Proc Natl Acad Sci U S A 2002; 99: 3052–7.

Abi-Habib RJ, Urieto JO, Liu S, Leppla SH, Duesbery NS, Frankel AE. BRAF status and mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 activity indicate sensitivity of melanoma cells to anthrax lethal toxin. Mol Cancer Ther 2005; 4: 1303–10.

Abi-Habib RJ, Singh R, Leppla SH, et al. Systemic anthrax lethal toxin therapy produces regressions of subcutaneous human melanoma tumors in athymic nude mice. Clin Cancer Res 2006; 12: 7437–43.

Park S, Leppla SH. Optimized production and purification of Bacillus anthracis lethal factor. Protein Expr Purif 2000; 18: 293–302.

Furge KA, Chen J, Koeman J, et al. Detection of DNA copy number changes and oncogenic signaling abnormalities from gene expression data reveals MYC activation in high-grade papillary renal cell carcinoma. Cancer Res 2007; 67: 3171–6.

Murphy DA, Makonnen S, Lassoued W, Feldman MD, Carter C, Lee WM. Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006). Am J Pathol 2006; 169: 1875–85.

Nomura T, Huang WC, Zhau HE, et al. β2-Microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMP-responsive element-binding protein, and vascular endothelial growth factor axis. Clin Cancer Res 2006; 12: 7294–305.

Aplin AE, Howe AK, Juliano RL. Cell adhesion molecules, signal transduction and cell growth. Curr Opin Cell Biol 1999; 11: 737–44.

Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol 1997; 9: 701–6.

Gold R, Schmied M, Giegerich G, et al. Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques. Lab Invest 1994; 71: 219–25.

Collins RJ, Harmon BV, Gobe GC, Kerr JF. Internucleosomal DNA cleavage should not be the sole criterion for identifying apoptosis. Int J Radiat Biol 1992; 61: 451–3.

Rousseau S, Houle F, Landry J, Huot J. p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 1997; 15: 2169–77.

Clauss M, Sunderkotter C, Sveinbjornsson B, et al. A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability. Blood 2001; 97: 1321–9.

Sodhi A, Montaner S, Patel V, et al. The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1α. Cancer Res 2000; 60: 4873–80.

Vasilevskaya I, O'Dwyer PJ. Role of Jun and Jun kinase in resistance of cancer cells to therapy. Drug Resist Updat 2003; 6: 147–56.

Qi M, Elion EA. MAP kinase pathways. J Cell Sci 2005; 118: 3569–72.

Enslen H, Raingeaud J, Davis RJ. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the map kinase kinases MKK3 and MKK6. J Biol Chem 1998; 273: 1741–8.

Depeille PE, Ding Y, Bromberg-White JL, Duesbery NS. MKK signaling and vascularization. Oncogene 2007; 26: 1290–6.

Milanini J, Vinals F, Pouyssegur J, Pages G. p42/p44 MAP kinase module plays a key role in the transcriptional regulation of the vascular endothelial growth factor gene in fibroblasts. J Biol Chem 1998; 273: 18165–72.

Petit AM, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 1997; 151: 1523–30.

Kirby JE. Anthrax lethal toxin induces human endothelial cell apoptosis. Infect Immun 2004; 72: 430–9.

Thông tin
Thông tin xuất bản

Cancer Research

Tập 68 Số 1

81-88

Thông tin tác giả