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

Lifeng Liu1, Ying Xu, Russel J Reiter

  • 1Department of Trauma Orthopaedics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology
|November 11, 2016
PubMed
Abstract

Insights

Melatonin inhibits osteosarcoma cell growth by blocking the ERK1/2 pathway, not p38, JNK, or Akt. This mechanism involves cell cycle arrest and reduced expression of key cell cycle proteins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Melatonin is known to inhibit MG-63 osteosarcoma cell proliferation.
  • The precise molecular mechanisms underlying melatonin's anticancer effects are not fully understood.
  • Mitogen-activated protein kinase (MAPK) and Akt signaling pathways are implicated in melatonin's anticancer actions.

Purpose of the Study:

  • To investigate the role of MAPK and Akt signaling pathways in melatonin's antiproliferative effects on human MG-63 osteosarcoma cells.
  • To determine if melatonin's inhibition of cell proliferation involves specific components of the MAPK pathway.

Main Methods:

  • Western blot analysis to assess protein phosphorylation and expression.
  • Flow cytometry with propidium iodide staining to analyze cell cycle phases.
  • Real-time PCR to quantify mRNA levels of cell cycle regulatory proteins.
  • Co-immunoprecipitation to study protein interactions.

Main Results:

  • Melatonin significantly inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) but did not affect p38, JNK, or Akt phosphorylation.
  • Melatonin treatment led to G1 and G2/M phase arrest in MG-63 cells.
  • Expression of cyclin D1, CDK4, cyclin B1, and CDK1 was downregulated by melatonin.
  • The combination of a MEK inhibitor (PD98059) and melatonin showed synergistic antiproliferative effects.
  • Melatonin and PD98059 blunted the interaction between phosphorylated ERK1/2 and key cell cycle proteins.

Conclusions:

  • Melatonin exerts its antiproliferative effects on MG-63 osteosarcoma cells primarily through the inhibition of the ERK1/2 signaling pathway.
  • The findings highlight the specific role of ERK1/2 inhibition in melatonin's anticancer activity, distinct from p38, JNK, or Akt pathways.
  • Melatonin's action involves cell cycle regulation and impacts the expression of critical cell cycle-related proteins.

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