Bitter Taste Signalling via TAS2R43 Enhances Temozolomide Efficacy in Glioblastoma Cells

Bitter taste receptors (TAS2Rs) are increasingly recognized as extraoral chemosensors that modulate diverse biological processes, including cancer cell behaviour and drug responsiveness. Many TAS2R ligands correspond to therapeutic compounds; however, their contribution to the response of brain tumours to chemotherapy remains unexplored. Here, we investigated whether the bitter taste signalling pathway is modulated by temozolomide (TMZ), the standard chemotherapeutic agent for glioblastoma, with an impact in treatment efficacy in glioblastoma cells. We show that TMZ elicits intracellular Ca²⁺ responses compatible with activation of GPCR signalling, and induces antiproliferative and pro-apoptotic effects in multiple human glioblastoma cell lines. Pharmacological inhibition of bitter taste receptors, as well as genetic silencing of the taste transduction G protein GNAT3, significantly attenuated TMZ-induced cytotoxicity, suggesting the involvement of bitter taste signalling in the process. In silico ligand prediction combined with receptor expression profiling identified TAS2R43 as a candidate mediator of these effects, and TAS2R43 knockdown markedly reduced TMZ-induced loss of cell viability, and apoptosis. Moreover, TMZ enhanced intracellular accumulation of the ABC transporter substrate doxorubicin, suggesting modulation of multidrug efflux mechanisms. Collectively, our findings identify TAS2R43 as a previously unrecognized modulator of glioblastoma responsiveness cells to TMZ and support a role for bitter taste signalling in shaping intracellular drug availability. These results highlight TAS2R43 as a potential biomarker and therapeutic leverage point to improve responses to TMZ and other ABC transporter-limited anticancer drugs.