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. 2021 Jan 15;7(1):12.
doi: 10.1038/s41420-020-00385-w.

"V体育官网入口" Secretoglobin 3A2 eliminates human cancer cells through pyroptosis

Shigetoshi Yokoyama #  1 , Shun Nakayama #  1 , Lei Xu  1 , Aprile L Pilon  2 , Shioko Kimura  3
Affiliations

Secretoglobin 3A2 eliminates human cancer cells through pyroptosis

Shigetoshi Yokoyama et al. Cell Death Discov. .

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 VSports手机版. 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. .

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Conflict of interest statement

A. L. P. is an employee of APCBio Innovations and has a 51% ownership interest in APCBio Innovations, which has an interest in commercializing the rhSCGB3A2. US Patent Application (No. 62/619,511) was filed for the work including those described in this study (S. K. , S. Y. ). S. N V体育安卓版. and L. X. declare no conflict of interest.

Figures (VSports)

Fig. 1
Fig. 1. Evaluation of the susceptibility to SCGB3A2-LPS and expression analysis of SDC1 and CASP4 in various human cancer cells.
A, B qPCR quantification of the relative expression levels for SDC1 (A) and CASP4 mRNA (B) in various human malignant cells. The expression level in A549 cells was arbitrarily set as 1.0. Graphs are representative of three independent experiments, each done in triplicate. C Combined qPCR results of A and B. Ranked order for CASP4 and SDC1 mRNA expression is indicated in the order from the highest to lowest, shown underneath the graph. The susceptibility to SCGB3A2 + LPS determined by CCK8 assay is shown as “y (observed)” or “– (not observed)“ in the CCK8 row. A bar for CASP4 and SDC1 mRNA of those susceptible to SCGB3A2 + LPS is indicated by dark blue (CASP4) and light blue (SDC1), respectively. D Correlation graph between SDC1 and CASP4 mRNA levels in 20 human cancer cells. Pearson correlation r = 0.7988, P < 0. 0001.
Fig. 2
Fig. 2. Examination of human cancer cells for cell growth and expression pattern of SDC1 and HS.
A Representative CCK8 analysis results. Average ± SD from more than three independent experiments. C, control; S2, SCGB3A2; L, LPS. *P < 0.05, **P < 0.01 by one-way ANOVA. B Representative immunofluorescence analysis. Counter stained with DAPI. Bar = 10 µm. White arrowheads indicate the membranous SDC1 expressions. C, D Flow cytometric analysis for SDC1 and HS expression on cell surfaces of human malignant cells using anti-SDC1 (C) and anti-HS antibody (D). Gray histograms indicate unstained negative control. Experiments were carried out more than three times and at each time, similar results were obtained.
Fig. 3
Fig. 3. Analysis of non-canonical inflammasome pathway.
A LDH cytotoxicity assay in the presence of LPS or SCGB3A2 alone, or the two together (SCGB3A2 + LPS). B LDH cytotoxicity assay in the presence of various amount of nigericin. Average ± SD from more than three independent experiments. *P < 0.01, **P < 0.0001 by Tukey’s multiple comparison. C Morphology of cells cultured in the presence of LPS or SCGB3A2 alone, SCGB3A2 + LPS, or nigericin for 3 h. For nigericin-treated group, cells were primed with LPS before addition of nigericin. Black arrow indicates ballooned cells, characteristic feature of pyroptosis. D Western blotting for the cleaved forms of CASP1 (p20), CASP4 (p20), and GSDMD (N-terminal). S: SCGB3A2, N: nigericin. Experiments were repeated more than twice and same results were obtained.
Fig. 4
Fig. 4. Inhibition of human cancer cells growth in vivo by SCGB3A2.
A Human cancer cells intravenous metastasis mouse model scheme. B, C Summary for the total tumor area of lung inoculated with human NSCLCs; NCI-H358, H157, H596 (B), and human colorectal cancer cells; HCT116 and SW620 (C). Averages ± SD from N = 5 per group for lung cancer cells and SW620, N = 8 for HCT116. Two sections at different positions of tissue per mouse were used for the analysis. *P < 0.05, **P < 0.01. Representative HE staining images of tissue sections from each PBS or SCGB3A2 administration group are shown on the right. Bar = 50 μm. D Representative images of TUNEL and CASP4 staining of lung sections of lung metastasized HCT116 cells from control (PBS) and SCGB3A2 administered mice. Three independent tissue samples were evaluated for each group, and similar results were obtained. Bar = 50 μm.
Fig. 5
Fig. 5. TCGA data analysis.
Survival curve for lung adenocarcinoma patients (n = 494) expressing higher SCGB3A2 (red, n = 49, top 10%) or lower SCGB3A2 (blue, n = 445, remaining 90%).
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