期刊
SCIENCE SIGNALING
卷 14, 期 677, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aax5971
关键词
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资金
- National Cancer Institute Molecular Imaging Center [P50 CA94056]
- Canadian Institute of Health Research Postdoctoral Fellowship
- Odyssey Postdoctoral Fellowship from MD Anderson Cancer Center
The myeloid-derived cells produce HOCl which inhibits IKK activity in melanoma tumor cells, leading to antitumor responses during early tumor growth. The MDC-derived HOCl mediates changes in gene expression and signaling pathways, enhancing immune response and reducing tumor growth.
The myeloperoxidase (MPO) system of myeloid-derived cells (MDCs) is central to cellular innate immunity. Upon MDC activation, MPO is secreted into phagosomes where it catalyzes the production of hypochlorous acid (HOCl), a potent chlorinating oxidant. Here, we demonstrated that the myeloid lineage-restricted MPO-HOCl system had antitumor effects in early melanoma growth in aged mice. Orthotopic melanomas grew more slowly in immunocompetent MPO+/+ host mice compared to age-matched syngeneic MPO-/- mice. Real-time intravital tumor imaging in vivo and in cell cocultures revealed a cell-cell proximity-dependent association between MDC-derived MPO enzyme activity and blockade of ligand-induced I.B. degradation in tumor cells. HOCl directly trans-inhibited I.B kinase (IKK) activity in tumor cells, thereby decreasing nuclear factor kappa B (NF-kappa B) transcriptional activation and inducing changes in the expression of genes involved in metabolic pathways, cell cycle progression, and DNA replication. By contrast, HOCl induced transcriptional changes in CD8(+) T cells related to ion transport and the MAPK and PI3K-AKT signaling pathways that are associated with T cell activation. MPO increased the circulating concentrations of the myeloid cell-attracting cytokines CXCL1 and CXCL5, enhanced local infiltration by CD8(+) cytotoxic T cells, and decreased tumor growth. Overall, these data reveal a role for MDC-derived HOCl as a small-molecule paracrine signaling factor that trans-inhibits IKK in melanoma tumor cells, mediating antitumor responses during early tumor progression.
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