The airway is continuously exposed to pathogens, including low levels of gram-negative bacteria in the air. Lipopolysaccharide (LPS) is a component of the outer membrane of gram-negative bacteria and can cause inflammation in the lung. It was previously thought that toll-like receptor 4 (TLR4) is the sole LPS-specific pattern recognition receptors (PRRs) at the cell membrane. However, recent studies demonstrated the presence of an TLR4-independent PRRs mechanism to sense LPS in the cytosol via an inflammatory caspase, caspase-11, in a non-canonical inflammasome pathway, resulting in pyroptosis (cell swelling, followed by rupture of cells). The activity of bacteria or endotoxin for anti-tumor effects has been extensively studied for decades since the first observation by W. B. Coley in 1891. Although Coley's toxin is currently not used for cancer treatment because of its toxicities, accumulating evidence has revealed that his theory was correct and the notion that the enhanced host immune systems by endotoxin could attack some cancer cells has advanced to cancer immunotherapy. However, whether endotoxin has a direct function in attacking cancer cells remains controversial, while the interest in endotoxin as a cancer therapeutic agent waned, despite of many reports for favorable outcomes. We found that SCGB3A2 chaperones LPS to the cytosol through the cell surface receptor syndecan-1 (SDC1) that belongs to a family of trans-membrane heparan sulfate proteoglycan; this leads to pyroptotic cell death driven by caspase-11. SCGB3A2 and LPS cotreatment 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, revealing one mechanism whereby LPS enters innate immune cells leading to pyroptosis, and clarifying the direct effect of LPS on cancer cells. The findings could potentially lead to new types of cancer treatments, particularly for lung cancers beyond the currently available treatments of surgery, radiotherapy, chemotherapy, and immunotherapy. The currently available cancer immunotherapy is mainly targeted to the host immune cells, whereas our study shows the possibility to directly target the activation of non-canonical inflammasome pathway of cancer cells. Combination of the cancer immunotherapy and the cancer cell self-destructive therapy could greatly advance the treatment of cancer patients. It remains to be examined, however, whether molecules that trigger pyroptosis, like LPS, could also be used to treat cancers other than those from the lung.
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