Related Experiment Video

Updated: Jun 19, 2026

MEDUSA for Identifying Death Regulatory Genes in Chemo-genetic Profiling Data
07:17

MEDUSA for Identifying Death Regulatory Genes in Chemo-genetic Profiling Data

Published on: February 7, 2025

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
PubMed

Insights

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.

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.

More Related Videos

Proximity Ligand Assay to Localize Proteins in DNA Damage Sites09:39

Proximity Ligand Assay to Localize Proteins in DNA Damage Sites

Published on: August 2, 2024

Yeast As a Chassis for Developing Functional Assays to Study Human P5314:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

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...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...