TY - JOUR
T1 - Myeloid cell derived HOCl is a paracrine effector that trans-inhibits IKK/NF-kB in melanoma cells and limits early tumor progression
AU - Liu, Tracy W.
AU - Gammon, Seth T.
AU - Yang, Ping
AU - Fuentes, David
AU - Worms, David Piwnica
N1 - Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/4/6
Y1 - 2021/4/6
N2 - 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 IkB degradation in tumor cells. HOCl directly trans-inhibited IkB kinase (IKK) activity in tumor cells, thereby decreasing nuclear factor kB (NF-kB) 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.
AB - 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 IkB degradation in tumor cells. HOCl directly trans-inhibited IkB kinase (IKK) activity in tumor cells, thereby decreasing nuclear factor kB (NF-kB) 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.
UR - http://www.scopus.com/inward/record.url?scp=85103995109&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103995109&partnerID=8YFLogxK
U2 - 10.1126/scisignal.aax5971
DO - 10.1126/scisignal.aax5971
M3 - Article
C2 - 33824181
AN - SCOPUS:85103995109
SN - 1945-0877
VL - 14
JO - Science signaling
JF - Science signaling
IS - 677
M1 - aax5971
ER -