Targeting the vasopressin type-2 receptor for renal cell carcinoma therapy

Abstract

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 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

A snake toxin as a theranostic agent for the type 2 vasopressin receptor

“…We exemplified this statement by generating the first PET agent specific to V2R and two highly efficient specific fluorescent probes, in vitro , to label native V2R ectopically expressed in cancer cell lines. Expression of V2R on cancer cells was also validated at the mRNA level and by immunostaining of fixed tissues 33 , 34 , 38 , but the antibody's specificity and capacity to bind to fresh cells is not documented, unlike in our study in which fluorescent MQ1 bound native, functional, extracellular V2R with high affinity and selectivity. 99 mTc-AVP was generated and proved able to label V2R in vitro 56 .…”

“…Ectopic expression of AVP and its receptors has been reported in numerous cancers 32 , 33 , with a potential anti-proliferative effect for V2R agonists in breast, pancreatic, colorectal and lung cancers 13 , 19 , 20 , 34 - 36 and an anti-proliferative effect for V2R antagonists in human renal carcinomas 33 . In this context, MQ1 as a specific V2R antagonist constitutes an interesting probe for imaging cancer cells overexpressing V2R.…”

Differential Expression of ADP/ATP Carriers as a Biomarker of Metabolic Remodeling and Survival in Kidney Cancers

“…Conversely, permeability problems and, at the same time, the indiscriminate toxicity of AAC inhibitors [ 4 , 23 ], able to target simultaneously AACs from several tissues, might be avoided by chemical conjugation of the CXT (and future CXT structurally related ligands) to a specific monoclonal antibody (mAb) directed against plasma membrane receptors expressed selectively on cancer cells [ 86 , 87 , 88 ]. The mAbs should grant the specific delivery of the investigated inhibitors to cancer cells expressing specific (or highly selective) receptors on the tumor cell surface.…”

Glycogen synthase kinase‐3β inhibits tubular regeneration in acute kidney injury by a FoxM1‐dependent mechanism

“…Mouse whole kidneys were homogenized, and cells were lysed in SDS Laemmli buffer and loaded onto 10% or 4%-20% gradient SDS-polyacrylamide agarose electrophoresis gels as described before. 29,30 Primary antibodies for FoxM1 (sc376471), c-Myc (sc764), p21 (sc6246) and GAPDH (sc32233) from Santa Cruz Biotechnology, and β-catenin (#9582S), Cyclin-D1 (#2978S), p27 (#3686S) and GSK3β (#9832S) from Cell Signaling Technology, Inc and β-actin (#A5441) from Millipore Sigma; secondary antibodies from Dako and ECL reagent from PerkinElmer (Netherlands) were used.…”

“…Cell viability was measured by MTT assay as described before. 30 Cell proliferation was measured using BrdU incorporation assay. HK2 cells plated on glass coverslips were treated with BrdU (#10280879001, Millipore Sigma) (3 µg/mL) for the final 3 hours of incubation, fixed and immunostained for BrdU using anti-BrdU antibody (#5292) as per above mentioned (immunofluorescence) procedure.…”