Clostridium botulinumneurotoxin A induces apoptosis and mitochondrial oxidative stress via activation of TRPM2 channel signaling pathway in neuroblastoma and glioblastoma tumor cells

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AKPINAR O., Ozsimsek A., Guzel M., NAZIROĞLU M.

JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION, vol.40, no.6, pp.620-632, 2020 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 40 Issue: 6
  • Publication Date: 2020
  • Doi Number: 10.1080/10799893.2020.1781174
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Chemical Abstracts Core, EMBASE, MEDLINE
  • Page Numbers: pp.620-632
  • Keywords: Apoptosis, Clostridium botulinumneurotoxin A, glioblastoma death, mitochondria oxidative stress, TRPM2 channel, BOTULINUM NEUROTOXIN, TOXIN-A, SUSCEPTIBILITY, PROLIFERATION, EXPOSURE, GENES
  • Süleyman Demirel University Affiliated: Yes


Background TheClostridium botulinumneurotoxin A (BTX) is a polypeptide produced by the bacteriumClostridium botulinum. In addition to the therapeutic actions of BTX against pain and neuromuscular disorders, it is acted as anticancerogenic effect through excessive mitochondria reactive oxygen species (ROS) production, apoptosis, and caspase activations. The TRPM2 cation channel is activated by ROS and ADP-ribose and it is inhibited by 2-aminoethyl diphenylborinate (2-APB) and N-(p-amylcinnamoyl) anthranilic acid (ACA). The aim of this study was an investigation of involvement BTX-induced TRPM2 activation on the mitochondria ROS production and apoptosis levels in the DBTRG glioblastoma and SH-SY5Y neuroblastoma tumor cells. Material and methods The DBTRG and SH-SY5Y cells were divided into four groups as control, BTX (5 IU for 24 h), BTX + ACA (25 mu M for 30 min), and BTX + 2-APB (100 mu M for 30 min). Results BTX treatment increased mitochondrial membrane depolarization (JC-1), mitochondrial (MitROS), and cytosolic (DHR123 and DCFH-DA) ROS levels, neuronal death (propidium iodide/Hoechst) rate, caspase -3, and -9 levels in the BTX group, although their levels were diminished in the BTX + ACA and BTX + 2-APB groups. The ACA and 2-APB treatments also decreased BTX-induced increase of TRPM2 cytosolic free Ca(2+)concentration in the glioblastoma and neuroblastoma cell death. Conclusions BTX caused neuroblastoma and glioblastoma tumor cell death by activating the mitochondria ROS productionviastimulating TRPM2 signaling pathways. BTX may serve as a potential therapeutic targetviaactivation of TRPM2 for treating glioblastoma and neuroblastoma cells.