Inhibition of G Protein-Coupled Receptor Kinase 2 Promotes Unbiased Downregulation of IGF1 Receptor and Restrains Malignant Cell Growth.
The ability of a receptor to preferentially activate only a subset of available downstream signal cascades is termed biased signaling. Although comprehensively recognized for the G protein-coupled receptors (GPCR), this process is scarcely explored downstream of receptor tyrosine kinases (RTK), including the cancer-relevant insulin-like growth factor-1 receptor (IGF1R). Successful IGF1R ... targeting requires receptor downregulation, yet therapy-mediated removal from the cell surface activates cancer-protective ?-arrestin-biased signaling (?-arr-BS). As these overlapping processes are initiated by the ?-arr/IGF1R interaction and controlled by GPCR-kinases (GRK), we explored GRKs as potential anticancer therapeutic targets to disconnect IGF1R downregulation and ?-arr-BS. Transgenic modulation demonstrated that GRK2 inhibition or GRK6 overexpression enhanced degradation of IGF1R, but both scenarios sustained IGF1-induced ?-arr-BS. Pharmacologic inhibition of GRK2 by the clinically approved antidepressant, serotonin reuptake inhibitor paroxetine (PX), recapitulated the effects of GRK2 silencing with dose- and time-dependent IGF1R downregulation without associated ?-arr-BS. In vivo, PX treatment caused substantial downregulation of IGF1R, suppressing the growth of Ewing's sarcoma xenografts. Functional studies reveal that PX exploits the antagonism between ?-arrestin isoforms; in low ligand conditions, PX favored ?-arrestin1/Mdm2-mediated ubiquitination/degradation of IGF1R, a scenario usually exclusive to ligand abundancy, making PX more effective than antibody-mediated IGF1R downregulation. This study provides the rationale, molecular mechanism, and validation of a clinically feasible concept for "system bias" targeting of the IGF1R to uncouple downregulation from signaling. Demonstrating system bias as an effective anticancer approach, our study reveals a novel strategy for the rational design or repurposing of therapeutics to selectively cross-target the IGF1R or other RTK. SIGNIFICANCE: This work provides insight into the molecular and biological roles of biased signaling downstream RTK and provides a novel "system bias" strategy to increase the efficacy of anti-IGF1R-targeted therapy in cancer.
Mesh Terms:
Animals, Apoptosis, Biomarkers, Tumor, Bone Neoplasms, Cell Proliferation, G-Protein-Coupled Receptor Kinase 2, G-Protein-Coupled Receptor Kinases, Gene Expression Regulation, Neoplastic, Humans, Insulin-Like Growth Factor I, Male, Mice, Mice, Nude, Phosphorylation, Receptor, IGF Type 1, Sarcoma, Ewing, Tumor Cells, Cultured, Ubiquitination, Xenograft Model Antitumor Assays
Animals, Apoptosis, Biomarkers, Tumor, Bone Neoplasms, Cell Proliferation, G-Protein-Coupled Receptor Kinase 2, G-Protein-Coupled Receptor Kinases, Gene Expression Regulation, Neoplastic, Humans, Insulin-Like Growth Factor I, Male, Mice, Mice, Nude, Phosphorylation, Receptor, IGF Type 1, Sarcoma, Ewing, Tumor Cells, Cultured, Ubiquitination, Xenograft Model Antitumor Assays
Cancer Res
Date: Dec. 15, 2020
PubMed ID: 33158816
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