Journal
BREAST CANCER RESEARCH AND TREATMENT
Volume 120, Issue 3, Pages 671-683Publisher
SPRINGER
DOI: 10.1007/s10549-009-0493-z
Keywords
NF-kappa B; Doxorubicin; Apoptosis; IL-8; FasL
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Funding
- Centre for DNA Fingerprinting and Diagnostics (CDFD)
- Council for Scientific & Industrial Research (CSIR), New Delhi
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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-kappa B) 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-kappa B 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 Ca2+, 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-kappa B 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.
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