title: Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo.
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-NH(2) 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.
authors.affiliation: Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Wang-Mei
authors.initials: WM
authors.lastname: Luo
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bender
authors.forename: Chao-Nan
authors.initials: CN
authors.lastname: Qian
authors.forename: Eric
authors.initials: E
authors.lastname: Kort
authors.forename: Zhong-Fa
authors.initials: ZF
authors.lastname: Zhang
authors.forename: Kristin
authors.initials: K
authors.lastname: VandenBeldt
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Duesbery
authors.forename: James H
authors.initials: JH
authors.lastname: Resau
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000942:Antigens, Bacterial; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; C030325:anthrax toxin; D020929:Mitogen-Activated Protein Kinase Kinases