Late phase activation of nuclear transcription factor kappaB by doxorubicin is mediated by interleukin-8 and induction of apoptosis via FasL
| Autor: | Charitha, Gangadharan, Maikho, Thoh, Sunil Kumar, Manna |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
TNF Receptor-Associated Factor 6
Proteasome Endopeptidase Complex Antibiotics Antineoplastic Fas Ligand Protein NFATC Transcription Factors Calcineurin Recombinant Fusion Proteins Interleukin-8 NF-kappa B Transcription Factor RelA Apoptosis Breast Neoplasms DNA Neoplasm Adenocarcinoma Neoplasm Proteins Gene Expression Regulation Neoplastic Doxorubicin Genes Reporter Cell Line Tumor Humans Female Calcium Signaling Proteasome Inhibitors bcl-2-Associated X Protein |
| Zdroj: | Breast cancer research and treatment. 120(3) |
| ISSN: | 1573-7217 |
| Popis: | Doxorubicin is one of the most effective molecules used in the treatment of various tumors. Contradictory reports often open windows to understand the doxorubicin-mediated signaling to exert its apoptosis effect. In this report, we provide evidences that doxorubicin induced biphasic induction of nuclear factor kappaB (NF-kappaB) of immediate activation followed by decrease in the amount of RelA (p65) subunit possibly by inducing the activity of proteasome, but not proteases. Further induction of NF-kappaB was observed through interleukin 8 (IL-8), expressed by doxorubicin treatment. Increased amount of IL-8 induced apoptosis via increase in the releases of intracellular Ca(2+), activation of calcineurin, nuclear translocation of nuclear factor activated T cell (NF-AT), and NF-AT-dependent FasL expression. Anti-IL-8 or -FasL antibody, dominant negative TRAF6 (TRAF6-DN), or TRAF6 binding peptide (TRAF6-BP) inhibited doxorubicin-mediated late phase induction of NF-kappaB and diminished cell death. Thus, our study clearly demonstrated that doxorubicin-mediated cell death is obtained through expression of IL-8. IL-8-mediated calcification is required for enhancement of doxorubicin-mediated cell death. Overall, this study will help to understand the much studied chemotherapeutic drug, doxorubicin-mediated cell signaling cascade to exert its effect during chemotherapy. |
| Databáze: | OpenAIRE |
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