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Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells

Sergiy Chornyy1, Yulia Parkhomenko2, Nataliya Chorna3,4

  • 1Department of Psychology, University of Haifa, Haifa, Israel.

Scientific Reports
|September 8, 2017
PubMed

Insights

Thiamine metabolism impairment activates the p53 protein, influencing gene expression and cell survival. This study reveals p53

Area of Science:

  • Cellular biology
  • Molecular biology
  • Neuroscience

Background:

  • Oxidative stress impacts cellular events, with p53 (tumor suppressor protein) playing a key role.
  • Thiamine (vitamin B1) metabolism is crucial for cellular energy and function.
  • The interplay between p53 and thiamine homeostasis requires further investigation.

Purpose of the Study:

  • To investigate the feedback loop between p53 transactivation and thiamine homeostasis.
  • To elucidate the role of p53 in regulating genes involved in thiamine metabolism and cellular stress response.
  • To determine the mechanism by which thiamine antagonist-induced stress affects p53 activity and downstream targets.

Main Methods:

  • Utilized neuronally differentiated SH-SY5Y cells.
  • Induced thiamine metabolism impairment using thiamine antagonists: amprolium (AM), oxythiamine (OT), and pyrithiamine (PT).
  • Assessed p53 gene expression, phosphorylation, DNA-binding activity, and the expression of thiamine transporter 1 (THTR1), pyruvate dehydrogenase E1 component subunit beta (PDHB), and oxoglutarate dehydrogenase (OGDH).
  • Employed decoy oligonucleotides to evaluate p53's role in gene transactivation.
  • Analyzed gene and metabolic networks to understand cell apoptosis pathways.

Main Results:

  • Exposure to AM, OT, and PT upregulated p53 expression and activity in SH-SY5Y cells.
  • Phosphorylation of p53 at Ser20 by all antagonists upregulated thiamine transporter 1 (THTR1) expression.
  • Dual phosphorylation of p53 at Ser9 and Ser20, induced by PT and OT, was necessary for upregulating pyruvate dehydrogenase E1 component subunit beta (PDHB) and oxoglutarate dehydrogenase (OGDH) expression.
  • p53 plays a significant role in the transactivation of THTR1, PDHB, and OGDH genes.
  • Oxythiamine (OT) induces apoptosis via the p53-dependent intrinsic pathway.

Conclusions:

  • Thiamine metabolism impairment activates p53 signaling.
  • p53 regulates key genes involved in thiamine transport and metabolism.
  • p53 mediates oxythiamine-induced apoptosis through the intrinsic pathway, highlighting a critical link between thiamine homeostasis and p53-driven cell fate.

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