Late phase activation of nuclear transcription factor kappaB by doxorubicin is mediated by interleukin-8 and induction of apoptosis via FasL.
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.
Gangadharan
Charitha
C
Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nampally, Hyderabad, 500001, India.
Thoh
Maikho
M
Manna
Sunil Kumar
SK
D000230:Adenocarcinoma / Q000473:pathology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000502:physiology; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
D000903:Antibiotics, Antineoplastic; C494826:BAX protein, human; D004273:DNA, Neoplasm; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D016209:Interleukin-8; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; C498143:RELA protein, human; D011993:Recombinant Fusion Proteins; D048029:TNF Receptor-Associated Factor 6; D051996:Transcription Factor RelA; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D019703:Calcineurin; D046988:Proteasome Endopeptidase Complex