Melatonin reduces lung cancer stemness through inhibiting of PLC, ERK, p38, β-catenin, and Twist pathways

Environ Toxicol. 2019 Feb;34(2):203-209. doi: 10.1002/tox.22674. Epub 2018 Nov 12.

Abstract

Lung cancer is one of the most common cancer in cancer-related deaths worldwide, which is characterized by its strong metastatic potential. The melatonin hormone secreted by the pineal grand has an antioxidant effect and protects cells against carcinogenic substances. However, the effects of melatonin in lung cancer stemness are largely unknown. We found that melatonin reduces CD133 expression by ~50% in lung cancer cell lines, while results of a sphere formation assay showed that melatonin inhibits lung cancer stemness. These effects of melatonin were reversed when the cell lines were incubated with phospholipase C (PLC), ERK/p38, and a β-catenin activator. Transfection with Twist siRNA augmented the inhibitory effects of melatonin, indicating that melatonin suppresses lung cancer stemness by inhibiting the PLC, ERK/p38, β-catenin, and Twist signaling pathways. We also found CD133 expression is positively correlated with Twist expression in lung cancer specimens. Melatonin shows promise in the treatment of lung cancer stemness and deserves further study.

Keywords: Twist; lung cancer; melatonin; stemness.

MeSH terms

  • A549 Cells
  • AC133 Antigen / genetics
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Humans
  • Lung Neoplasms / pathology*
  • MAP Kinase Signaling System / drug effects
  • Melatonin / pharmacology*
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Signal Transduction / drug effects*
  • Twist Transcription Factors / antagonists & inhibitors
  • Type C Phospholipases / antagonists & inhibitors
  • beta Catenin / antagonists & inhibitors

Substances

  • AC133 Antigen
  • Twist Transcription Factors
  • beta Catenin
  • Type C Phospholipases
  • Melatonin