title: Melatonin inhibits MMP-9 transactivation and renal cell carcinoma metastasis by suppressing Akt-MAPKs pathway and NF-κB DNA-binding activity.
abstract: 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.
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yung-Wei
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Liang-Ming
authors.initials: LM
authors.lastname: Lee
authors.affiliation: Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Medical Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Jiunn
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chih-Ying
authors.initials: CY
authors.lastname: Chu
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Peng
authors.initials: P
authors.lastname: Tan
authors.affiliation: Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Medical Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004273:DNA, Neoplasm; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; C498143:RELA protein, human; D051996:Transcription Factor RelA; D051057:Proto-Oncogene Proteins c-akt; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D008550:Melatonin
keywords: Akt; MMPs; NF-κB; melatonin; metastasis; renal cell carcinoma