Hypoxia-induced decrease in p53 protein level and increase in c-jun DNA binding activity results in cancer cell resistance to etoposide
| Autor: | Noelle Ninane, Jean-Philippe Cosse, Carine Michiels, Martine Raes, Marie Ronvaux |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Small interfering RNA Proto-Oncogene Proteins c-jun Blotting Western Apoptosis Biology lcsh:RC254-282 Proto-Oncogene Proteins c-myc Cell Line Tumor medicine Humans Transcription factor Etoposide Oligonucleotide Array Sequence Analysis Tumor hypoxia Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling c-jun NF-kappa B Hypoxia (medical) lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Antineoplastic Agents Phytogenic Cell Hypoxia DNA-Binding Proteins Drug Resistance Neoplasm Cancer cell Cancer research RNA Interference medicine.symptom Tumor Suppressor Protein p53 medicine.drug Protein Binding Research Article |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 11, Iss 10, Pp 976-986 (2009) |
| ISSN: | 1476-5586 1522-8002 |
| Popis: | Tumor hypoxia is one of the features of tumor microenvironment that contributes to chemoresistance in particular by cellular adaptations that modulate the apoptotic process. However, the mechanisms involved in this resistance still need deeper understanding. In this study, we investigated the involvement of four transcription factors, c-Myc, nuclear factor κB (NF-κB), p53, and c-jun/activator protein 1 (AP-1) in the hypoxia-induced resistance to etoposide in HepG2 cells. Whereas the profile of c-Myc and NF-κB activity did not fit the effect of hypoxia on caspase 3 activity, hypoxia decreased basal p53 abundance and DNA binding activity as well as p53 etoposide-induced activation. Short interfering RNA (siRNA) silencing evidenced that p53 was required for etoposide-induced apoptosis under normoxia. An inhibition of its activity under hypoxia could thus be responsible at least in part for the protection observed under hypoxic conditions. Moreover, p53 was found to induce the expression of Bak1. We showed that Bak1 was involved in the etoposide-induced apoptosis because Bak1 siRNA decreased it. Conversely, hypoxia increased c-jun DNA binding activity in the presence of etoposide. siRNA-mediated silencing of c-jun increased the responsiveness of cells to etoposide under hypoxia, as shown by an increase in caspase 3 activity and lactate dehydrogenase release. These effects occurred in a p53-independent manner. These data evidenced that hypoxia decreased the responsiveness of HepG2 cells to etoposide at least by two independent pathways involving p53 inhibition and c-jun activation. Copyright © 2009 Neoplasia Press, Inc. All rights reserved. |
| Databáze: | OpenAIRE |
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