May 5, 2020

Characterization of GRK5 as a novel regulator of rhabdomyosarcoma tumor cell growth and self-renewal

Oncotarget
Thao PhamEleanor Y Chen

Abstract

Rhabdomyosarcoma (RMS) is the most common soft-tissue pediatric sarcoma. Clinical outcomes for RMS patients with relapsed or metastatic disease remain poor. Treatment options remain limited, presenting an urgent need for novel therapeutic targets. Using a high-throughput siRNA screen against the human kinome, we identified GRK5, a G-protein receptor kinase, as a novel regulator of RMS tumor cell growth and self-renewal. Through functional assays in vitro and in vivo, we show that GRK5 regulates cell cycle in a kinase-independent manner to promote RMS tumor cell growth. NFAT1 expression is regulated by GRK5 in a kinase independent manner, and loss of NFAT1 phenocopies GRK5 loss-of-function effects on the cell cycle alterations. Self-renewal of tumor propagating cells (TPCs) is thought to give rise to tumor relapse. We show that loss of GRK5 results in a significant reduction of RMS self-renewal capacity in part due to increased cell death. Treatment of human RMS xenografts in mice with CCG-215022, a GRK5-selective inhibitor, results in reduced tumor growth and self-renewal in both major subtypes of RMS. GRK5 represents a novel therapeutic target for the treatment of RMS.

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Mentioned in this Paper

Cell Growth
Receptors for Activated C Kinase
High-Throughput Screening Assays
Rhabdomyosarcoma
Pseudomonas sp. CCG
Laboratory mice
Protein KINASE
Neoplasm Metastasis
Stem Cell Self-Renewal
GRK5 gene

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