Inhibition of G protein-coupled receptor kinase 2 promotes unbiased downregulation of IGF-1 receptor and restrains malignant cell growth

Caitrin Crudden, Takashi Shibano, Dawei Song, Mihnea P Dragomir, Sonia Cismas, Julianna Serly, Daniela Nedelcu, Enrique Fuentes-Mattei, Andrei Tica, George A Calin, Ada Girnita, Leonard Girnita

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The ability of a receptor to preferentially activate only a subset of available downstream signal cascades is termed biased signaling. While 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 (IGF-1R). Successful IGF-1R targeting requires receptor downregulation, yet therapy-mediated removal from the cell surface activates cancer-protective β-arrestin-biased signaling (β-arr-BS). As these overlapping processes are initiated by the β-arr/IGF-1R interaction and controlled by GPCR-kinases (GRK), we explored GRKs as potential anti-cancer therapeutic targets to disconnect IGF-1R downregulation and β-arr-BS. Transgenic modulation demonstrated that GRK2-inhibition or GRK6-overexpression enhanced degradation of IGF-1R, but both scenarios sustained IGF-1-induced β-arr-BS. Pharmacological inhibition of GRK2 by the clinically approved antidepressant, serotonin reuptake inhibitor paroxetine (PX), recapitulated the effects of GRK2-silencing with dose- and time-dependent IGF-1R downregulation without associated β-arr-BS. In vivo, PX-treatment caused substantial downregulation of IGF-1R, suppressing the growth of Ewing's sarcoma xenografts. Functional studies reveal that PX exploits the antagonism between β-arrestin isoforms: in low ligand conditions, PX favored β-arrestin1/Mdm2-mediated ubiquitination/degradation of IGF-1R, a scenario usually exclusive to ligand abundancy, making PX more effective than antibody-mediated IGF-1R downregulation. This study provides the rationale, molecular mechanism, and validation of a clinically feasible concept for 'system bias' targeting of the IGF-1R to uncouple downregulation from signaling. Demonstrating system bias as an effective anti-cancer approach, our study reveals a novel strategy for the rational design or repurposing of therapeutics to selectively cross-target the IGF-1R or other RTK.

Original languageEnglish
Number of pages15
JournalCancer Research
Volume81
Issue number2
Early online date6 Nov 2020
DOIs
Publication statusPublished - 15 Jan 2021

Cite this