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.
