https://scholars.lib.ntu.edu.tw/handle/123456789/161567
標題: | Melatonin inhibits MMP-9 transactivation and renal cell carcinoma metastasis by suppressing Akt-MAPKs pathway and NF-B DNA-binding activity | 作者: | Lin, Yung-Wei Lee, Liang-Ming Lee, Wei-Jiunn Chu, Chih-Ying Tan, Peng Yang, Yi-Chieh Chen, Wei-Yu Yang, Shun-Fa Hsiao, Michael Chien, Ming-Hsien |
關鍵字: | Akt;melatonin;metastasis;MMPs;NF-B;renal cell carcinoma | 公開日期: | 2016 | 卷: | 60 | 期: | 3 | 起(迄)頁: | 277-290 | 來源出版物: | J. Pineal Res. | 摘要: | Renal cell carcinoma (RCC) is the most lethal of all urological malignancies because of its potent metastasis potential. Melatonin exerts multiple tumor-suppressing activities through antiproliferative, proapoptotic, and anti-angiogenic actions and has been tested in clinical trials. However, the antimetastastic effect of melatonin and its underlying mechanism in RCC are unclear. In this study, we demonstrated that melatonin at the pharmacologic concentration (0.5-2 mm) considerably reduced the migration and invasion of RCC cells (Caki-1 and Achn). Furthermore, we found that melatonin suppressed metastasis of Caki-1 cells in spontaneous and experimental metastasis animal models. Mechanistic investigations revealed that melatonin transcriptionally inhibited MMP-9 by reducing p65- and p52-DNA-binding activities. Moreover, the Akt-mediated JNK1/2 and ERK1/2 signaling pathways were involved in melatonin-regulated MMP-9 transactivation and cell motility. Clinical samples revealed an inverse correlation between melatonin receptor 1A (MTNR1A) and MMP-9 expression in normal kidney and RCC tissues. In addition, a higher survival rate was found in MTNR1A(high)/MMP-9(low) patients than in MTNR1A(low)/MMP-9(high) patients. Overall, our results provide new insights into the role of melatonin-induced molecular regulation in suppressing RCC metastasis and suggest that melatonin has potential therapeutic applications for metastastic RCC. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/280126 | DOI: | 10.1111/jpi.12308 | SDG/關鍵字: | gelatinase B; immunoglobulin enhancer binding protein; melatonin; melatonin 1 receptor; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase p38; protein kinase B; protein p52; stress activated protein kinase 1; synaptotagmin I; DNA; gelatinase B; immunoglobulin enhancer binding protein; melatonin; MMP9 protein, human; NFKB2 protein, human; protein kinase B; RELA protein, human; transcription factor RelA; animal experiment; animal model; animal tissue; Article; cancer tissue; cell migration; cell motility; concentration response; controlled study; drug mechanism; experimental metastasis; human; human cell; kidney carcinoma; male; metastasis; metastasis inhibition; mouse; nonhuman; protein DNA binding; protein expression; signal transduction; survival rate; transactivation; tumor invasion; animal; biosynthesis; drug effects; drug screening; gene expression regulation; genetics; HL-60 cell line; kidney carcinoma; kidney tumor; metabolism; metastasis; nonobese diabetic mouse; pathology; SCID mouse; transcription initiation; Animals; Carcinoma, Renal Cell; DNA, Neoplasm; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Kidney Neoplasms; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Melatonin; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; NF-kappa B p52 Subunit; Proto-Oncogene Proteins c-akt; Transcription Factor RelA; Transcriptional Activation; Xenograft Model Antitumor Assays |
顯示於: | 腫瘤醫學研究所 |
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