Secretoglobin 3A2 eliminates human cancer cells through pyroptosis

Shun Nakayama,Shioko Kimura,Lei Xu,Aprile L Pilon,Shigetoshi Yokoyama

doi:10.1038/s41420-020-00385-w

Abstract

Non-canonical inflammasome activation that recognizes intracellular lipopolysaccharide (LPS) causes pyroptosis, the inflammatory death of innate immune cells. The role of pyroptosis in innate immune cells is to rapidly eliminate pathogen-infected cells and limit the replication niche in the host body. Whether this rapid cell elimination process of pyroptosis plays a role in elimination of cancer cells is largely unknown. Our earlier study demonstrated that a multi-functional secreted protein, secretoglobin (SCGB) 3A2, chaperones LPS to cytosol, and activates caspase-11 and the non-canonical inflammasome pathway, leading to pyroptosis. Here we show that SCGB3A2 exhibits marked anti-cancer activity against 5 out of 11 of human non-small cell lung cancer cell lines in mouse xenographs, while no effect was observed in 6 of 6 small cell lung cancer cell lines examined. All SCGB3A2-LPS-sensitive cells express syndecan 1 (SDC1), a SCGB3A2 cell surface receptor, and caspase-4 (CASP4), a critical component of the non-canonical inflammasome pathway. Two epithelial-derived colon cancer cell lines expressing SDC1 and CASP4 were also susceptible to SCGB3A2-LPS treatment. TCGA analysis revealed that lung adenocarcinoma patients with higher SCGB3A2 mRNA levels exhibited better survival. These data suggest that SCGB3A2 uses the machinery of pyroptosis for the elimination of human cancer cells via the non-canonical inflammasome pathway, and that SCGB3A2 may serve as a novel therapeutic to treat cancer, perhaps in combination with immuno and/or targeted therapies.

Highlights

Inflammasomes are multimeric protein complexes that function as one of the pattern recognition receptors (PPRs) to activate proinflammatory caspases[1]
Differential syndecan 1 (SDC1) and CASP4 expression patterns determine the effect of secretoglobin family 3A member 2 (SCGB3A2) in human cancer cell lines Previously, we showed that Lewis lung carcinoma (LLC) cells have high expression of SDC1 and CASP11, with strong susceptibility to SCGB3A2-induced anti-tumor activity, whereas B16F10 melanoma cells have very little expression of SDC1 and CASP11, and no susceptibility to SCGB3A217
To examine if this correlation is found in human cancer cells, a panel of 20 human cancer-derived cell lines (17 lung, 2 colon, and 1 cervix) were analyzed for the constitutive expression of mRNA encoding SDC1 and CASP4 (CASP4 and CASP5 are the human equivalent of CASP11 in mice) (Fig. 1A–C)

Summary

Introduction

Inflammasomes are multimeric protein complexes that function as one of the pattern recognition receptors (PPRs) to activate proinflammatory caspases[1]. While TLR4 (Toll-like receptor 4) is a well-known PPRrecognizing extracellular lipopolysaccharides (LPS), the inflammasome is a PPR which recognizes microbederived molecules present in cytosol and activates the pyroptosis pathway. The physiological significance of pyroptosis is that severely microbe-infected cells can be rapidly eliminated from the host, resulting in a limited milieu where infectious agents can thrive and expand their colonization[9]. Pyroptosis promotes pathogens clearance by acting as an alarm signal through release of IL1B/IL18, and other factors that attract immune cells to the infectious sites in the host body[3].

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Conclusion