Inhibition of ERK1/2 Signaling Pathway is Involved in Melatonin's Antiproliferative Effect on Human MG-63 Osteosarcoma Cells

Lifeng Liu, Ying Xu, Russel J. Reiter, Yutao Pan, Di Chen, Yangzhou Liu, Xingyu Pu, Liguo Jiang, Zengchun Li

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Background: In a previous study, we found that melatonin inhibits MG-63 osteosarcoma cell proliferation; however, the underlying mechanisms remain elusive. Mitogen-activated protein kinase (MAPK) and Akt signaling pathways play key roles in the anticancer effects of melatonin. Aims: The present study investigated whether MAPK and Akt signaling pathways are involved in melatonin's antiproliferative actions on the human MG-63 osteosarcoma cells. Methods/Results: Western blot analysis confirmed that melatonin significantly inhibited phosphorylation of ERK1/2 but not p38, JNK, or Akt. The expression of ERK1/2, p38, JNK, and Akt was not altered by melatonin. PD98059 and melatonin alone, and especially in combination, significantly inhibited cell proliferation. The changes included G 1 and G 2 /M phase arrest of the cell cycle, and a downregulation of the expression at both the protein and mRNA levels of cyclin D1 and CDK4 (related to the G 1 phase) and of cyclin B1 and CDK1 (related to the G 2 /M phase) as measured by flow cytometry after propidium iodide staining, and both western blot and real-time PCR, respectively. Furthermore, the combination of PD98059 and melatonin synergistically and markedly augmented the action of either agent alone. Co-immunoprecipitation further confirmed that there was an interaction between p-ERK1/2 and cyclin D1, CDK4, cyclin B1, or CDK1, which was blunted in the presence of melatonin or PD98059. Conclusion: These findings suggest that melatonin's antiproliferative action is mediated by inhibition of the ERK1/2 signaling pathway rather than the p38, JNK, or Akt pathways.

Original languageEnglish (US)
Pages (from-to)2297-2307
Number of pages11
JournalCellular Physiology and Biochemistry
Volume39
Issue number6
DOIs
StatePublished - Nov 1 2016

Keywords

  • Cell cycle
  • ERK1/2
  • Melatonin
  • Osteosarcoma

ASJC Scopus subject areas

  • Physiology

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