Melatonin suppresses lung cancer metastasis by inhibition of epithelial-mesenchymal transition through targeting to Twist

Clin Sci (Lond). 2019 Mar 15;133(5):709-722. doi: 10.1042/CS20180945. Print 2019 Mar 15.

Abstract

The epithelial-mesenchymal transition (EMT) phenotype, whereby mature epithelial cells undergo phenotype transition and differentiate into motile, invasive cells, has been indicated in tumor metastasis. The melatonin hormone secreted by the pineal gland has an antioxidant effect and protects cells against carcinogenic substances that reduce tumor progression. However, the effects of melatonin in EMT and lung cancer metastasis are largely unknown. We found that melatonin down-regulated EMT by inhibiting Twist/Twist1 (twist family bHLH transcription factor 1) expression. This effect was mediated by MT1 receptor, PLC, p38/ERK and β-catenin signaling cascades. Twist expression was positively correlated with tumor stage and negatively correlated with MT1 expression in lung cancer specimens. Furthermore, melatonin inhibited EMT marker expression and lung cancer metastasis to liver in vivo Finally, melatonin shows promise in the treatment of lung cancer metastasis and deserves further study.

Keywords: EMT; Lung cancer; Melatonin; Twist.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Movement / drug effects*
  • Epithelial-Mesenchymal Transition / drug effects*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / prevention & control*
  • Liver Neoplasms / secondary
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Melatonin / pharmacology*
  • Mice, SCID
  • Neoplasm Invasiveness
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Receptor, Melatonin, MT1 / agonists
  • Receptor, Melatonin, MT1 / metabolism
  • Signal Transduction
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism*
  • Type C Phospholipases / metabolism
  • Xenograft Model Antitumor Assays
  • beta Catenin / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • CTNNB1 protein, human
  • Nuclear Proteins
  • Receptor, Melatonin, MT1
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • beta Catenin
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Type C Phospholipases
  • Melatonin