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

Abstract

Copyright: Pham et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.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.

Targeting GRK5 for Treating Chronic Degenerative Diseases

“…Finally, in rhabdomyosarcoma tumor cells, GRK5 has been proposed as a novel regulator of growth and self-renewal. Indeed, this kinase was able to regulate NFAT1 expression, in a kinase-independent manner, thus promoting tumor cell growth [ 104 ].…”

“…In addition to the study of GRK5 inhibitors on cardiomyocytes, studies have explored the therapeutic potential of GRK5 inhibitors in cancer, and specifically, for the prevention of GRK5-dependent tumor progression. For example, Pham et al have demonstrated that treatment of mice with human rhabdomyosarcoma xenografts, with CCG-215022, a selective GRK5 inhibitor, resulted in a significant reduction of tumor growth [ 104 ]. Moreover, a recent study by Sommer et al investigated the effect of sunitinib, a potent small-molecule inhibitor, on GRK5 and breast cancer cells [ 122 ].…”