Arginine vasopressin (AVP) and its type-2 receptor (V2R) play an essential role in the regulation of salt and water homeostasis by the kidneys. V2R activation also stimulates proliferation of renal cell carcinoma (RCC) cell lines in vitro. The current studies investigated V2R expression and activity in human RCC tumors, and its role in RCC tumor growth. Examination of the cancer genome atlas (TCGA) database, and analysis of human RCC tumor tissue microarrays, cDNA arrays and tumor biopsy samples demonstrated V2R expression and activity in clear cell RCC (ccRCC). In vitro, V2R antagonists OPC31260 and Tolvaptan, or V2R gene silencing reduced wound closure and cell viability of 786-O and Caki-1 human ccRCC cell lines. Similarly in mouse xenograft models, Tolvaptan and OPC31260 decreased RCC tumor growth by reducing cell proliferation and angiogenesis, while increasing apoptosis. In contrast, the V2R agonist dDAVP significantly increased tumor growth. High intracellular cAMP levels and ERK1/2 activation were observed in human ccRCC tumors. In mouse tumors and Caki-1 cells, V2R agonists reduced cAMP and ERK1/2 activation, while dDAVP treatment had the reverse effect. V2R gene silencing in Caki-1 cells also reduced cAMP and ERK1/2 activation. These results provide novel evidence for a pathogenic role of V2R signaling in ccRCC, and suggest that inhibitors of the AVP-V2R pathway, including the FDA-approved drug Tolvaptan, could be utilized as novel ccRCC therapeutics.
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We thank the University of Kansas Cancer Center Biospecimen Core (P30 CA168524) and the PKD Biomarkers and Biomaterials Core (P30-DK106912) for human specimens, and the Flow Cytometry Core (P30 GM103326 NIH/NIGMS COBRE grant) of University of Kansas Medical Center.
This study was supported by NIH R01-DK083525, a private donation from the Watts family and a Pilot and Feasibility Grant from the KU Cancer Center and PKD Research and Translation Core Center P30-DK106912 to RR. ND is supported by Postdoctoral Fellowship Grants from the KU Biomedical Research and Training Program and American Heart Association.
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Sinha, S., Dwivedi, N., Tao, S. et al. Targeting the vasopressin type-2 receptor for renal cell carcinoma therapy. Oncogene 39, 1231–1245 (2020). https://doi.org/10.1038/s41388-019-1059-0