Melatonin inhibits MMP-9 transactivation and renal cell carcinoma metastasis by suppressing Akt-MAPKs pathway and NF-κB DNA-binding activity

Yung Wei Lin, Liang Ming Lee, Wei Jiunn Lee, Chih Ying Chu, Peng Tan, Yi Chieh Yang, Wei Yu Chen, Shun Fa Yang, Michael Hsiao, Ming Hsien Chien

Research output: Contribution to journalArticle

86 Citations (Scopus)

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 MTNR1Ahigh/MMP-9low patients than in MTNR1Alow/MMP-9high 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.

Original languageEnglish
Pages (from-to)277-290
Number of pages14
JournalJournal of Pineal Research
Volume60
Issue number3
DOIs
Publication statusPublished - Apr 1 2016

Keywords

  • Akt
  • melatonin
  • metastasis
  • MMPs
  • NF-κB
  • renal cell carcinoma

ASJC Scopus subject areas

  • Endocrinology

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