Bitter Taste Signalling via TAS2R43 Enhances Temozolomide Efficacy in Glioblastoma Cells

Area of Science:

• Molecular Biology
• Cancer Research
• Neuro-oncology

Background:

• Bitter taste receptors (TAS2Rs) function as extraoral chemosensors influencing cancer cell behavior and drug response.
• The role of TAS2Rs in brain tumor response to chemotherapy, specifically glioblastoma's response to temozolomide (TMZ), is largely unexplored.

Purpose of the Study:

• To investigate if the bitter taste signaling pathway is modulated by temozolomide (TMZ) in glioblastoma cells.
• To determine the impact of this modulation on glioblastoma treatment efficacy.

Main Methods:

• Assessed intracellular Ca2+ responses to TMZ in glioblastoma cells.
• Utilized pharmacological inhibition and genetic silencing (GNAT3, TAS2R43) to evaluate the role of bitter taste signaling.
• Employed in silico ligand prediction and receptor expression profiling to identify candidate TAS2Rs.
• Investigated TMZ's effect on doxorubicin accumulation via ABC transporters.

Main Results:

• TMZ induced anti-proliferative and pro-apoptotic effects in glioblastoma cells, linked to G-protein-coupled receptor signaling.
• Inhibition or silencing of TAS2Rs and GNAT3 attenuated TMZ-induced cytotoxicity.
• TAS2R43 was identified as a key modulator; its knockdown significantly reduced TMZ's anti-cancer effects.
• TMZ enhanced doxorubicin accumulation, suggesting modulation of multidrug efflux mechanisms.

Conclusions:

• Bitter taste signaling, particularly involving TAS2R43, plays a significant role in glioblastoma cell response to TMZ.
• TAS2R43 may serve as a potential biomarker for predicting response to TMZ.
• Targeting TAS2R43 could offer a strategy to enhance the efficacy of TMZ and other anticancer drugs limited by ABC transporter activity.