Journal Article

A novel pathway of LPS uptake through syndecan-1 leading to pyroptotic cell death

Pilon, Aprile L, Kimura, Shioko, Cai, Yan, Yokoyama, Shigetoshi, Tomita, Takeshi, Xu, Lei, Yoneda, Mitsuhiro, Cachau, Raul E, Murata, Miyuki

2018

Overview

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. Inflammation serves to kill invading bacteria and viruses. Certain molecules on the surface of the microbes can trigger an inflammatory cascade, and one example of such a molecule is lipopolysaccharide (LPS). Cells can react to LPS by triggering a process called pyroptosis that causes the cell to burst and die. The released cell contents attract blood and lymphatic cells that in turn kill the LPS-producing bacteria. This prevents the bacteria from multiplying and spreading. LPS was used in the very early days of medicine to treat cancer, although it has fallen out of favor because it causes severe side effects, such as a hyperinflammatory response (sepsis) that can result in death. It was not known exactly how LPS kills cancer cells, which has limited its use. Yokoyama et al. now show that a protein called SCGB3A2, which is produced by the cells that line the lung airways, binds to LPS. Tests on mouse immune cells and lung cancer cells grown in the laboratory showed that the resulting SCGB3A2-LPS complex can then bind to a cell surface protein called syndecan 1. This enables LPS to enter the cell and trigger pyroptosis and cell death. To confirm the role of SCGB3A2 in pyroptosis, Yokoyama et al. examined tumor growth in mice that are not able to produce SCGB3A2. These mice developed more tumors than normal mice, but tumor growth was suppressed when mice were injected with SCGB3A2. The findings presented by Yokoyama et al. could potentially lead to new types of cancer treatments, particularly for lung cancers. However, it remains to be examined whether molecules that trigger pyroptosis, like LPS, could also be used to treat cancers other than those from the lung. Further work is also needed to understand in more detail how SCGB3A2 and LPS work together to cause cancer cell death.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Bacteria / Biological Transport / Cancer / cancer cell death / Carcinoma, Lewis Lung - drug therapy / Carcinoma, Lewis Lung - genetics / Carcinoma, Lewis Lung - immunology / Carcinoma, Lewis Lung - mortality / Caspase / Caspase-11 / Caspases - genetics / Caspases - immunology / Caspases, Initiator / Cell death / Cell growth / Cell Line, Tumor / Cell proliferation / Cell surface / Chaperones / Cytosol / Cytotoxicity / Gene Expression Regulation, Neoplastic / Humans / Immune system / Immunity, Innate / Immunology and Inflammation / Inflammasomes / Inflammation / Innate immunity / Laboratories / Lipopolysaccharides / Lipopolysaccharides - pharmacology / LPS / Lungs / Lymphatic Metastasis / Macrophages / Male / Melanoma, Experimental - drug therapy / Melanoma, Experimental - genetics / Melanoma, Experimental - immunology / Melanoma, Experimental - mortality / Metastasis / Mice / Mice, Transgenic / non-canonical infammasome pathway / Protein Array Analysis / Proteins / Pyroptosis / Pyroptosis - drug effects / Pyroptosis - genetics / Pyroptosis - immunology / RAW 264.7 Cells / RNA, Small Interfering - genetics / RNA, Small Interfering - immunology / secretoglobin3A2 / Secretoglobins - antagonists & inhibitors / Secretoglobins - genetics / Secretoglobins - immunology / Signal Transduction / Statistical analysis / Survival Analysis / Syndecan / syndecan-1 / Syndecan-1 - antagonists & inhibitors / Syndecan-1 - genetics / Syndecan-1 - immunology / Toll-Like Receptor 4 - antagonists & inhibitors / Toll-Like Receptor 4 - genetics / Toll-Like Receptor 4 - immunology / Tumors / Xenograft Model Antitumor Assays / Xenografts