Chemosensory role of intracellular TAS2Rs, the activation of which triggers drug excretion by ABCB1 in cancer cells.

Anticancer drug resistance is a significant obstacle in chemotherapy. Although ABCB1, an ABC transporter, confers chemoresistance owing to the extrusion of drugs out of cells, ABCB1 blockers have not been developed. Here, we clarified the chemosensory role of bitter taste receptors (TAS2Rs) in response to incorporated drugs. The underlying mechanisms by which ABCB1 is regulated in cancer cells involve TAS2Rs, the activation of which triggers drug excretion by ABCB1. In MCF-7 cells, intracellular TAS2Rs were activated by incorporated substances, which elicited the Gα12/13/RhoA/ROCK/p38MAPK/NF-κB pathway, leading to ABCB1 upregulation. We validated that prolonged exposure of MCF-7 cells to TAS2R ligands helps defend against harmful compounds. These cells exhibit rapid excretion of substances and predominant growth in the presence of toxic drugs. This predominance disappeared after treatment with verapamil, an ABCB1 blocker, suggesting the involvement of ABCB1. We further determined that TAS2R14, one of TAS2Rs, is a receptor for doxorubicin, an anticancer drug. In MCF-7 cells, TAS2R14-deficiency diminished doxorubicin-induced ABCB1 production, resulting in higher sensitivity to doxorubicin than in control cells. Altogether, intracellular TAS2Rs act as gatekeepers that drive drug excretion. Blockers for TAS2R14 could be used as efficacious agents to attenuate the excretion of doxorubicin, resulting in escape from doxorubicin resistance.