Inhibition of MAPK Kinase Signaling Pathways Suppressed Renal Cell Carcinoma Growth and Angiogenesis In vivo

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]

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Cancer Research

Tập 68 Số 1

81-88

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