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Melatonin inhibits MMP‐9 transactivation and renal cell carcinoma metastasis by suppressing Akt‐MAPKs pathway and NF‐κB DNA‐binding activity
Authors: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
Affiliation:1. Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan;2. Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan;3. Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;4. Department of Medical Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan;5. Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan;6. Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan;7. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan;8. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan;9. Genomics Research Center, Academia Sinica, Taipei, Taiwan
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.
Keywords:Akt  melatonin  metastasis  MMPs  NF‐κ  B  renal cell carcinoma
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