Myeloid cell–derived HOCl is a paracrine effector that trans-inhibits IKK/NF-κB in melanoma cells and limits early tumor progression
- 6 April 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 14 (677)
- https://doi.org/10.1126/scisignal.aax5971
Abstract
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 IκBα degradation in tumor cells. HOCl directly trans-inhibited IκB kinase (IKK) activity in tumor cells, thereby decreasing nuclear factor κB (NF-κB) 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.Keywords
Funding Information
- National Cancer Institute (P50 CA94056)
- National Cancer Institute (P30 CA016672)
- National Cancer Institute (P30 CA125123)
- University of Texas MD Anderson Cancer Center
- UVA Cancer Center
- National Cancer Institute Molecular Imaging Center (P50 CA94056)
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