Abstract
Intracellular lipopolysaccharide (LPS) triggers the non-canonical inflammasome pathway, resulting in pyroptosis of innate immune cells. In addition to its well-known proinflammatory role, LPS can directly cause regression of some tumors, although the underlying mechanism has remained unknown. Here we show that secretoglobin(SCGB)3A2, a small protein predominantly secreted in airways, chaperones LPS to the cytosol through the cell surface receptor syndecan-1; this leads to pyroptotic cell death driven by caspase-11. SCGB3A2 and LPS co-treatment significantly induced pyroptosis of macrophage RAW264.7 cells and decreased cancer cell proliferation in vitro, while SCGB3A2 treatment resulted in reduced progression of xenograft tumors in mice. These data suggest a conserved function for SCGB3A2 in the innate immune system and cancer cells. These findings demonstrate a critical role for SCGB3A2 as an LPS delivery vehicle; they reveal one mechanism whereby LPS enters innate immune cells leading to pyroptosis, and they clarify the direct effect of LPS on cancer cells.
Keywords:
LPS; cancer cell death; immunology; inflammation; mouse; non-canonical infammasome pathway; pyroptosis; secretoglobin3A2; syndecan-1.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Biological Transport
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Carcinoma, Lewis Lung / drug therapy*
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Carcinoma, Lewis Lung / genetics
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Carcinoma, Lewis Lung / immunology
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Carcinoma, Lewis Lung / mortality
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Caspases / genetics
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Caspases / immunology
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Caspases, Initiator
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Cell Line, Tumor
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Gene Expression Regulation, Neoplastic*
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Humans
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Immunity, Innate
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Lipopolysaccharides / pharmacology*
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Lymphatic Metastasis
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Male
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Melanoma, Experimental / drug therapy*
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Melanoma, Experimental / genetics
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Melanoma, Experimental / immunology
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Melanoma, Experimental / mortality
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Mice
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Mice, Transgenic
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Protein Array Analysis
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Pyroptosis / drug effects
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Pyroptosis / genetics
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Pyroptosis / immunology
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RAW 264.7 Cells
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RNA, Small Interfering / genetics
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RNA, Small Interfering / immunology
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Secretoglobins / antagonists & inhibitors
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Secretoglobins / genetics*
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Secretoglobins / immunology
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Signal Transduction
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Survival Analysis
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Syndecan-1 / antagonists & inhibitors
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Syndecan-1 / genetics*
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Syndecan-1 / immunology
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Toll-Like Receptor 4 / antagonists & inhibitors
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Xenograft Model Antitumor Assays
Substances
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Lipopolysaccharides
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RNA, Small Interfering
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Scgb3a2 protein, mouse
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Sdc1 protein, mouse
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Secretoglobins
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Syndecan-1
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Casp4 protein, mouse
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Caspases
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Caspases, Initiator