Characterization of GRK5 as a novel regulator of rhabdomyosarcoma tumor cell growth and self-renewal
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Thao Pham1, Kristin Robinson1, Terra Vleeshouwer-Neumann1, James E. Annis2 and Eleanor Y. Chen1
1 Department of Pathology, University of Washington, Seattle, WA, USA
2 Quellos HTS Core, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
|Eleanor Y. Chen,||email:||[email protected]|
Keywords: rhabdomyosarcoma; self-renewal; GRK5, kinase; cell cycle
Received: December 05, 2019 Accepted: April 03, 2020 Published: April 21, 2020
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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