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Effect of pH on radiation-induced p53 expression
Eun Kyung Choi1, Kenneth P Roberts, Robert J Griffin
1Department of Therapeutic Radiology, College of Medicine, University of Ulsan, Seoul, Korea.
International Journal of Radiation Oncology, Biology, Physics
|November 3, 2004
Summary
An acidic tumor microenvironment enhances radiation-induced p53 expression by increasing p53 formation and slowing degradation. This suggests implications for radiotherapy response in acidic tumors.
Area of Science:
- Oncology
- Molecular Biology
- Radiation Biology
Background:
- Tumor microenvironments are often acidic.
- The tumor suppressor protein p53 plays a critical role in cellular responses to DNA damage, including radiation-induced damage.
- Understanding how the acidic tumor microenvironment affects p53 signaling is crucial for cancer therapy.
Purpose of the Study:
- To investigate the impact of an acidic extracellular environment on radiation-induced p53 expression and related molecular signaling pathways.
- To elucidate the mechanisms by which acidity influences p53 stability and transcriptional activity following irradiation.
Main Methods:
- Human colorectal cancer cells (RKO.C) with wild-type p53 were cultured in standard (pH 7.5) or acidic (pH 6.6) media.
- Cells were exposed to gamma irradiation.
- p53 and p53 mRNA expression, p53 degradation rates, p53 transcriptional activity (using a reporter construct), Mdm2 expression, and p53 phosphorylation were analyzed.
Main Results:
- Acidic conditions (pH 6.6) prolonged radiation-induced expression of p53 and p53 mRNA.
- Transcriptional activity of p53 and p53 degradation were extended in the acidic environment.
- Radiation-induced Mdm2 expression was suppressed, while p53 phosphorylation increased in acidic conditions.
- These changes suggest inhibited p53-Mdm2 complex formation.
Conclusions:
- Acidic extracellular environments significantly enhance radiation-induced p53 expression.
- This enhancement occurs through increased p53 formation and delayed degradation, partly due to inhibited p53-Mdm2 complex formation.
- The findings highlight the potential role of the acidic tumor microenvironment in modulating tumor response to radiotherapy, warranting further investigation.