Selumetinib Inhibits Melanoma Metastasis to Mouse Liver via Suppression of EMT-targeted Genes
- Authors
- Ryu, Seung-Hee; Heo, Seung-Ho; Park, Eun Young; Choi, Kyung-Chul; Ryu, Je-Won; Lee, Seok Ho; Lee, Sang-Wook
- Issue Date
- Feb-2017
- Publisher
- INT INST ANTICANCER RESEARCH
- Keywords
- MEK inhibitor; selumetinib (AZD6244); liver metastasis; melanoma; EMT
- Citation
- ANTICANCER RESEARCH, v.37, no.2, pp.607 - 614
- Journal Title
- ANTICANCER RESEARCH
- Volume
- 37
- Number
- 2
- Start Page
- 607
- End Page
- 614
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/6472
- DOI
- 10.21873/anticanres.11354
- ISSN
- 0250-7005
- Abstract
- Aim: We investigated the therapeutic effects of a mitogen-activated protein (MEK) inhibitor, selumetinib, in a hepatic melanoma metastasis model and studied its possible mechanism of action. Materials and Methods: Melanoma cell lines were exposed to selumetinib under different experimental conditions. We established a mouse model of liver metastasis and treated mice orally with vehicle or selumetinib and then evaluated metastasis progress. Results: Growth inhibition was observed in melanoma cells as a consequence of G(1)-phase cell-cycle arrest and the subsequent induction of apoptosis in a doseand time-dependent manner. Mice with established liver metastases that were treated with selumetinib exhibited significantly less tumor progression than vehicle-treated mice. c-Myc expression in metastasized liver tissues were suppressed by selumetinib. Moreover, oral treatment with selumetinib modulated expression of epithelial-tomesenchymal transition-and metastasis-related genes, including integrin alpha-5 (ITGA5), jagged 1 (JAG1), zinc finger E-box-binding homeobox 1 (ZEB1), NOTCH, and serpin peptidase inhibitor clade E (SERPINE1). Conclusion: We established a mouse model of hepatic metastasis using a human melanoma cell line, such models are essential in elucidating the therapeutic effects of anti-metastatic drugs. Our data suggest the possibility that selumetinib presents a new strategy to treat liver metastasis in patients with melanoma by suppressing epithelial-to-mesenchymal transition-related genes.
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