Abstract
BackgroundInterleukin-8 (IL-8) is a cytokine that plays an important role in tumor progression in a variety of cancer types; however, its regulation is not well understood in oral cancer cells. In the present study, we examined the expression and mechanism of IL-8 in which it is involved by treating immortalized (IHOK) and malignant human oral keratinocytes (HN12) cells with deferoxamine (DFO).MethodsIL-8 production was measured by an enzyme-linked immunoabsorbent assay and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Electrophoretic mobility shift assays was used to determine NF-κB binding activity. Phosphorylation and degradation of the I-κB were analyized by Western blot.ResultsIHOK cells incubated with DFO showed increased expression of IL-8 mRNA, as well as higher release of the IL-8 protein. The up-regulation of DFO-induced IL-8 expression was higher in IHOK cells than in HN12 cells and was concentration-dependent. DFO acted additively with IL-1β to strongly up-regulate IL-8 in IHOK cells but not in HN12 cells. Accordingly, selective p38 and ERK1/2 inhibitors for both kinases abolished DFO-induced IL-8 expression in both IHOK and HN12 cells. Furthermore, DFO induced the degradation and phosphorylation of IκB, and activation of NF-κB. The IL-8 inducing effects of DFO were mediated by a nitric oxide donor (S-nitrosoglutathione), and by pyrrolidine dithiocarbamate, an inhibitor of NF-κB, as well as by wortmannin, which inhibits the phosphatidylinositol 3-kinase-dependent activation of NAD(P)H oxidase.ConclusionThis results demonstrate that DFO-induced IL-8 acts via multiple signaling pathways in immortalized and malignant oral keratinocytes, and that the control of IL-8 may be an important target for immunotheraphy against human oral premalignant lesions.
Highlights
Interleukin-8 (IL-8) is a cytokine that plays an important role in tumor progression in a variety of cancer types; its regulation is not well understood in oral cancer cells
[27] We reported that p38 and extracellular-regulated kinases (ERKs) mitogenactivated protein (MAP) kinase mediated DFO-induced apoptosis and the suppression of differentiation in immortalized human oral keratinocytes (IHOK) and oral cancer cells [28]; an immunomodulatory role of IL-8 against the iron chelator DFO has not been reported in oral cancer and IHOK cells
Effects of Iron chelators on IL-8 expression in IHOK and HN12 cells We examined whether chelation of iron from immortalized human oral keratinocyte (IHOK) and oral squamous cell carcinoma cells (HN12) was sufficient to induce a signal that would increase the production IL-8
Summary
Interleukin-8 (IL-8) is a cytokine that plays an important role in tumor progression in a variety of cancer types; its regulation is not well understood in oral cancer cells. Several chemotherapy regimes have been clinically applied to treat oral-pharyngeal cancers, but none have shown to significantly improve prognoses [3,4]. Iron has a major effect on neoplastic cell growth due to its catalytic effect on the formation of hydroxyl radicals, its suppression of the activity of host defense cells, and its role in the promotion of cancer cell multiplication [6,7]. Iron chelation by deferoxamine (DFO), a bacterial siderophore, has been shown to inhibit the growth of and/or to induce apoptosis in malignant leukemia, neuroblastoma, melanoma, hepatoma, Kaposi's sarcoma, and cervical cancer cell lines [8,9,10,11,12,13,14]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call