The molecular mechanism of GADD153 in apoptosis of keloid fibroblasts exposed to botulinum toxin type A

J Cell Mol Med. 2021 Oct;25(19):9402-9410. doi: 10.1111/jcmm.16881. Epub 2021 Sep 2.

Abstract

Apoptosis plays a key role in keloids. Growth arrest and DNA damage-inducible gene 153 (GADD153) is regulated by apoptosis. Botulinum toxin type A (BTXA) can induce apoptosis in keloid fibroblasts. This research aimed to explore the hypothesis that GADD153 mediates apoptosis in keloid fibroblasts exposed to BTXA. BTXA significantly induced GADD153 protein and mRNA expression in keloid fibroblasts. Treatment with c-Jun N-terminal kinase (JNK) inhibitor SP600125, JNK small interfering RNA (siRNA) and tumour necrosis factor-alpha (TNF-α) antibodies reversed the BTXA-induced GADD153 expression. BTXA enhanced the transcriptional activity of GADD153, whereas the GADD153 mutant plasmid, JNK siRNA and anti-TNF-α antibody treatment abolished the BTXA-induced transcriptional activity of GADD153. The addition of TNF-α to keloid fibroblasts markedly increased GADD153 protein expression. The addition of GADD153 siRNA, SP600125 and anti-TNF-α antibodies reversed cell death and caspase 3 and 9 activity induced by BTXA.

Keywords: Botulinnum Toxin type A; GADD153; apoptosis; keloid fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / genetics*
  • Botulinum Toxins, Type A / pharmacology*
  • Cell Line
  • Cells, Cultured
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism*
  • Gene Expression
  • Gene Expression Regulation / drug effects
  • Humans
  • Keloid / genetics*
  • Keloid / metabolism
  • Models, Biological
  • Promoter Regions, Genetic
  • Transcription Factor CHOP / genetics*
  • Transcription Factor CHOP / metabolism
  • Transcriptional Activation / drug effects
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Tumor Necrosis Factor-alpha
  • Transcription Factor CHOP
  • Botulinum Toxins, Type A