Aspirin inhibits proliferation and promotes differentiation of neuroblastoma cells via p21 Waf1 protein up-regulation and Rb1 pathway modulation

J Cell Mol Med. 2019 Oct;23(10):7078-7087. doi: 10.1111/jcmm.14610. Epub 2019 Aug 20.

Abstract

Several clinical and experimental studies have demonstrated that regular use of aspirin (acetylsalicylic acid, ASA) correlates with a reduced risk of cancer and that the drug exerts direct anti-tumour effects. We have previously reported that ASA inhibits proliferation of human glioblastoma multiforme-derived cancer stem cells. In the present study, we analysed the effects of ASA on nervous system-derived cancer cells, using the SK-N-SH (N) human neuroblastoma cell line as an experimental model. ASA treatment of SK-N-SH (N) dramatically reduced cell proliferation and motility, and induced neuronal-like differentiation, indicated by the appearance of the neuronal differentiation marker tyrosine hydroxylase (TH) after 5 days. ASA did not affect cell viability, but caused a time-dependent accumulation of cells in the G0 /G1 phase of the cell cycle, with a concomitant decrease in the percentage of cells in the G2 phase. These effects appear to be mediated by a COX-independent mechanism involving an increase in p21Waf1 and underphosphorylated retinoblastoma (hypo-pRb1) protein levels. These findings may support a potential role of ASA as adjunctive therapeutic agent in the clinical management of neuroblastoma.

Keywords: Rb1; acetylsalicylic acid; cell cycle; neuroblastoma; neuronal differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspirin / pharmacology*
  • Cell Cycle / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Differentiation / drug effects*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Humans
  • Models, Biological
  • Neuroblastoma / pathology*
  • Phosphorylation / drug effects
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Retinoblastoma / metabolism*
  • Signal Transduction* / drug effects
  • Survivin / metabolism
  • Up-Regulation / drug effects*

Substances

  • BIRC5 protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Survivin
  • Prostaglandin-Endoperoxide Synthases
  • Aspirin