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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
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Hypoxia-induced decrease in p53 protein level and increase in c-jun DNA binding activity results in cancer cell

Jean-Philippe Cosse1, Marie Ronvaux, Noëlle Ninane

  • 1Laboratory of Biochemistry and Cellular Biology (URBC), FUNDP-University of Namur, 5000 Namur, Belgium.

Neoplasia (New York, N.Y.)
|October 2, 2009
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Summary

Hypoxia, low oxygen in tumors, causes chemoresistance by inhibiting p53 and activating c-jun, reducing etoposide effectiveness in HepG2 cells. Understanding these pathways is key to overcoming treatment resistance.

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Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • Tumor hypoxia is a key factor in chemoresistance, modulating apoptosis.
  • Mechanisms underlying hypoxia-induced chemoresistance require further elucidation.
  • Transcription factors play crucial roles in cellular responses to microenvironmental stress.

Purpose of the Study:

  • Investigate the role of c-Myc, NF-kappaB, p53, and c-jun/AP-1 in hypoxia-induced etoposide resistance.
  • Determine the specific pathways through which hypoxia affects etoposide sensitivity in HepG2 cells.
  • Identify potential therapeutic targets to overcome chemoresistance in hypoxic tumors.

Main Methods:

  • HepG2 cells were exposed to hypoxia and etoposide.
  • Activity of transcription factors (c-Myc, NF-kappaB, p53, c-jun) was assessed.
  • Short interfering RNA (siRNA) was used to silence p53 and c-jun.
  • Apoptosis was measured by caspase 3 activity and lactate dehydrogenase release.

Main Results:

  • Hypoxia decreased p53 abundance and DNA binding activity, impairing etoposide-induced apoptosis.
  • p53 was essential for etoposide-induced apoptosis under normoxia.
  • Hypoxia increased c-jun DNA binding activity, contributing to etoposide resistance.
  • Silencing c-jun restored etoposide sensitivity under hypoxia in a p53-independent manner.
  • Bak1 was identified as a downstream target of p53 involved in etoposide-induced apoptosis.

Conclusions:

  • Hypoxia confers etoposide resistance in HepG2 cells via p53 inhibition and c-jun activation.
  • These two pathways operate independently to reduce cellular responsiveness to etoposide.
  • Targeting p53 and c-jun may offer strategies to enhance chemotherapy efficacy in hypoxic tumors.