βArrestin2 Mediates Renal Cell Carcinoma Tumor Growth.

Renal Cell Carcinoma (RCC) is one of the most lethal urological cancers worldwide. The disease does not present early clinical symptoms and is commonly diagnosed at an advanced stage. Limited molecular drivers have been identified for RCC, resulting in the lack of effective treatment for patients with progressive disease. Ubiquitous βArrestin2 (βArr2) is well established for its function in the desensitization and trafficking of G protein-coupled receptors. More recently, βArr2 has been implicated in the regulation of fundamental cellular functions, including proliferation and invasion. We used bioinformatic and genetic approaches to determine role of βArr2 in RCC tumor growth. Analysis of published human datasets shows that ARRB2 (gene encoding βArr2) expression is increased in RCC tumor compared to normal tissue and that high levels of ARRB2 correlate with worse patient survival. Experimentally, we show that knockout of ARRB2 decreases rate of RCC cell proliferation and migration in vitro and xenograft tumor growth in animals. Mechanistically, βArr2 regulates c-Src activity, Cyclin A expression and cell cycle progression that are involved in tumor growth. These results show that βArr2 is a critical regulator of RCC tumor growth and suggest its utility as a potential marker and drug target to treat advanced disease.