Abstract 5999: Bitter taste receptors trigger pyroptosis and apoptosis through NLRP3 activation in oral cancer cells in response to a dysbiotic bacterial molecule: A possible role as pattern recognition receptors

Abstract

Abstract Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancers. It has been reported that the composition of the oral microbiome was shifted in OSCC patients compared to healthy subjects. In particular, Pseudomonas aeruginosa is one of the most abundant oral microbes in OSCC patients. Bitter taste receptors (taste 2 receptors, TAS2Rs), known as G protein-coupled receptors (GPCRs), can recognize P. aeruginosa-derived quorum sensing molecules, such as N-(3-oxododecanoyl)-L-homoserine lactone (oxo-C12). Therefore, we explored the role of TAS2Rs in oral dysbiosis and cancers. Herein, we observed that TAS2Rs, such as TAS2R4, TAS2R14, and TAS2R38, mediated both pyroptosis and apoptosis, two distinct types of programmed cell death, in human OSCC HSC3 cells exposed to oxo-C12. Unexpectedly, TAS2Rs provoked pyroptosis and apoptosis in a GPCR-independent manner. Instead, TAS2Rs seemed to recruit NLRP3 inflammasome and subsequently activate caspase-8 in response to oxo-C12, implying the TAS2Rs-NLRP3-caspase-8 axis. Notably, the immunofluorescence staining showed considerable expression of TAS2Rs and NLRP3 in oxo-C12-treated HSC3 cells as well as human OSCC tissues, further supporting the presence of the alternative activation pathway of TAS2Rs. Moreover, siRNA knockdown of MyD88 diminished oxo-C12-induced NLRP3 activation, caspase-8 cleavage and cell death marker expression, which implies that MyD88 is involved in activation of the TAS2Rs-NLRP3-caspase-8 axis. This also suggests that TAS2Rs might function as potential pattern recognition receptors, similar to toll-like receptors responsible for recognition of pathogen and their molecules. Based on The Cancer Genome Atlas analysis, downregulation of TAS2Rs was correlated with poor prognosis in OSCC patients. Taken together, TAS2Rs might trigger the host defense mechanism against microbial dysbiosis-induced cancer development. Thus, TAS2Rs could be promising chemotherapeutic targets for OSCC treatment, particularly via disconnecting interkingdom molecular links between microbial alterations and carcinogenesis. Citation Format: Seong Yu, Heesu Lee, Jeong Mu Shin, Na-Young Song. Bitter taste receptors trigger pyroptosis and apoptosis through NLRP3 activation in oral cancer cells in response to a dysbiotic bacterial molecule: A possible role as pattern recognition receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5999.