Kidney Week

Abstract: FR-PO247

Inhibition of Vasopressin Type 2 Receptor Signaling Suppresses Tumor Growth in Renal-Cell Carcinoma

Session Information

• Apoptosis, Proliferation, Autophagy, Cell Senescence, Cell Transformation
  November 03, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Fluid, Electrolytes, and Acid-Base

• 702 Water/Urea/Vasopressin, Organic Solutes

Authors

• Sinha, Sonali, university of kansas medical center, Kansas City, Kansas, United States

Sonali Sinha,

• Dwivedi, Nidhi, University of Kansas Medical Center, Kansas City, Kansas, United States

Nidhi Dwivedi,

• Rao, Reena, University of Kansas Medical Center, Kansas City, Kansas, United States

Reena Rao,

Background

Renal cell carcinoma (RCC) accounts for 90% of all kidney cancers and is among the 10 most common cancers worldwide. Clear-cell and papillary-cell RCC represent 70-75% cases of all RCC. Clear cell RCC tumors originate from the renal proximal tubules that express vasopressin type 1 receptors (V₁R). However, in human clear cell RCC tumors we detected V₂R expression and V₂R mediated cell signaling. Since V₂R activity promotes cell proliferation in polycystic kidney disease, we hypothesized that V₂R activity is pathogenic in RCC, and V₂R inhibition can suppress tumor growth

Methods

In Caki-1 and 786-0 cells, we determined the effect of V₂R antagonist OPC31260 on cell viability, cell cycle, colonogenecity and cell migration. The effect of OPC31260 on tumor development was tested in female athymic nude mice. Mice were subcutaneously inoculated with a 100-μl suspension of Caki-1 cells. When tumor volume reached 80-100 mm³ mice were randomized into groups (n=8) to receive vehicle or OPC31260, injected intraperitoneally daily for 28 days. Tumors volumes were measured and mice were weighed on alternate days. Tumors were harvested and weighed at the end of the study and portions were fixed in 10% formalin or snap frozen for protein and mRNA estimation.

Results

OPC31260 treatment dose dependently and significantly reduced cell viability, colony formation and cell migration. At higher doses of OPC31260, G2M cell cycle arrest was observed. In the mouse xenograft model, within 28 days of start of treatment, tumor volume increased by 9-folds in vehicle treated mice, while in the OPC31260 treated mice, less than 2-folds increase in tumor volume was observed. Tumor weights at sacrifice were 10- folds lesser in OPC31260 treated mice compared to vehicle treated mice. OPC31260 treatment significantly reduced pERK1/2 and pCREB levels compared to vehicle treated mice, suggesting suppression of V₂R signaling. Cell proliferation, detected by BRDU incorporation in the tumors was significantly reduced in OPC31260 treated mice and apoptosis detected by TUNEL assay was significantly high.

Conclusion

Vasopressin-V₂R signaling plays a pathogenic role in tumor progression in RCC and suppression of V₂R signaling by OPC31260 can suppress tumor growth in RCC. Hence V₂R is a novel target for therapy in RCC.

Funding

• NIDDK Support