Abstract 5912: Bitter taste receptors link between microbiome dysbiosis and programmed cell death in oral squamous cell carcinoma

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 was enriched in the oral cavity of OSCC patients. Bitter taste receptors (taste 2 receptors, TAS2Rs), known as G protein-coupled receptors (GPCRs), can recognize quorum sensing molecules, such as N-(3-oxododecanoyl)-L-homoserine lactone (oxo-C12) secreted from P. aeruginosa. Based on The Cancer Genome Atlas analysis, downregulation of TAS2Rs was correlated with poor prognosis in various cancers. This prompted us to investigate the role of TAS2Rs in oral dysbiosis and cancers. Here, we found that TAS2Rs mediated both apoptosis and pyroptosis, distinct types of programmed cell death, in response to oxo-C12, in OSCC cell lines. Of note, it was blocked by knockdown of TAS2R4, 14, or 38. Unexpectedly, TAS2Rs-mediated apoptosis and pyroptosis were GPCR-independent. Given our observation that the blockade of NLRP3 inflammasome attenuated oxo-C12-induced OSCC cell death, TAS2Rs seem to recruit NLRP3 inflammasome rather than G protein signaling pathway in order to mediate the programmed cell death in OSCC. Once NLRP3 is activated, caspase-8 triggered both apoptosis and pyroptosis in response to oxo-C12, supporting the role of TAS2Rs-NLRP3-caspase-8 axis. Interestingly, siRNA knockdown of MyD88 diminished oxo-C12-induced programmed cell death, implying the possible involvement of MyD88 in the TAS2Rs-NLRP3-caspase-8 axis. Taken together, bitter taste receptors promote the programmed cell death of OSCC in response to oral dysbiosis through activation of NLRP3 inflammasome, which further supports TAS2Rs as prognostic markers in OSCC. Thus, these results will shed light on better understanding of interplay between microbiome and cancer, proposing TAS2Rs as novel therapeutic targets in oral dysbiosis-induced OSCC development. Citation Format: Byeong-Oh Hwang, Se-Young Park, Na-Young Song. Bitter taste receptors link between microbiome dysbiosis and programmed cell death in oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5912.