Role of Novel Cytokine Secretoglobin (SCGB) 3A2 in Lung

Division Of Basic Sciences - Nci

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Abstract

Previously we found that SCGB3A2 is a lipopolysaccharide (LPS) binding protein, and SCGB3A2-LPS complex binds to a cell surface receptor syndecan-1 (SDC1), and endocytosed cytosolic LPS binds to caspase-11 and activates the non-canonical inflammasome pathway, resulting in pyroptosis. Mouse Lewis lung carcinoma cells had high expression of SDC1 and caspase-11 (CASP11) with strong susceptibility to SCGB3A2-induced growth inhibitory activity while B16F10 melanoma cells had very little expression of SDC1 and CASP11 with no susceptibility to SCGB3A2. These results indicated that the SDC1/CASP11 expression patterns could determine the susceptibility of cancer cells to SCGB3A2-induced anti-tumor activity. Twenty human cancer-derived cell lines (17 lung, 2 colon, and 1 cervix) were examined by in vitro cell culture analysis in the presence of LPS and in vivo xenografts mouse model experiments without additional LPS (endogenous LPS was sufficient), to see if the tumor growth was affected by SCGB3A2. Five out of 11 human non-small cell lung cancer (NSCLC) and two epithelial-derived colon cancer cell lines showed decreased growth by in vitro assays and in mouse xenograft model with administration of SCGB3A2, while no effect was observed in 6 of 6 small cell lung cancer (SCLC) cell lines. All SCGB3A2 sensitive cells expressed SDC1 and caspase-4 (CASP4), a human equivalent to mouse CASP11, a critical component of the non-canonical inflammasome pathway. Lung adenocarcinoma patients with higher SCGB3A2 mRNA levels exhibited better survival by TCGA analysis. Recently, the use of pyroptosis pathway as a cancer treatment has been gaining attention, however, little research has been carried out. SCGB3A2 may serve as a novel therapeutic to treat cancer, perhaps in combination with immuno and/or targeted therapies. Our current research focuses on the use of monophosphoryl lipid A(MPLA), the endotoxin principle of LPS to use instead of LPS in the study of SCGB3A2-LPS anti-cancer activity. LPS is a notorious pro-inflammatory agent, and is a heterogeneous preparation containing large aggregates with various molecular weights, which is not well-suited for studying the nature of SCGB3A2-LPS interaction. In contrast, MPLA is a small molecule, and is safe and widely used as a vaccine adjuvant in humans, suggesting a better alternative to LPS in the study of SCGB3A2-LPS interaction and in vivo studies. SCGB3A2-MPLA interaction is currently being studied using biochemical, biophysical, and cell biological techniques. We also study the effect of SCGB3A2 on COVID-19 infected cells. The plasma level of Interleukin-1beta, a notable cytokine released upon pyroptosis is reported to be elevated in COVID-19 patients, suggesting that pyroptosis is activated in cells infected with SARS-CoV-2. It is known that several of SARS-CoV encoded proteins activate NLRP3, a major player in pyroptosis, while some others are involved in inhibitory reaction of innate immunity. Since SARS-CoV-2 and SARS-CoV share 80% sequence identity, it would be possible that SARS-CoV-2 infection may involve pyroptosis activation, and SCGB3A2 may have the potential to regulate the innate immune response to SARS-CoV-2. Our immediate aim is to determine whether SARS-CoV-2 encoded proteins have any role in canonical and/or non-canonical inflammasome pathways resulting in pyroptosis, and whether SCGB3A2 plays a role in regulating the non-canonical pathway in SARS-CoV-2 infection. We have been preparing adenovirus expressing several SARS-CoV-2 encoded proteins that may be responsible for pyroptotic pathway. The study on the effect of SCGB3A2 on regulating the pyroptotic pathway is ongoing.