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Significance The G protein–coupled bile acid receptor (GPBAR) is the native bile acid receptor and therapeutic target for treating metabolic diseases. However, specific bile acids are suspected to promote cancer… Click to show full abstract
Significance The G protein–coupled bile acid receptor (GPBAR) is the native bile acid receptor and therapeutic target for treating metabolic diseases. However, specific bile acids are suspected to promote cancer progression. We showed that different Gs/arrestin-biased signaling of GPBAR played key roles in non–small cell lung cancer (NSCLC) cell viability. Specifically, β-arrestin–biased GPBAR agonist R399 stimulated cell growth through promoting YAP (Yes-associate Protein) activation. Conversely, GPBAR activation triggered by deoxycholic acid and INT-777, which showed a preference to Gs signaling, inhibited cancer cell progression. Moreover, we delineated key structural determinants of β-arrestin bias and protumor activity of GPBAR and identified that phosphorylation of GPBAR by GRK2/GRK5 contributed to β-arrestin–biased signaling. These results may facilitate rational design of GPBAR-targeting drugs with anticancer benefits.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2022
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