Abstract
BackgroundIncreased serum level of parathyroid hormone (PTH) was found in metastatic prostate cancers. Calcimimetic R-568 was reported to reduce PTH expression, to suppress cell proliferation and to induce apoptosis in parathyroid cells. In this study, we investigated the effect of R-568 on cellular survival of prostate cancer cells.MethodsProstate cancer cell lines LNCaP and PC-3 were used in this study. Cellular survival was determined with MTT, trypan blue exclusion and fluorescent Live/Death assays. Western blot assay was utilized to assess apoptotic events induced by R-568 treatment. JC-1 staining was used to evaluate mitochondrial membrane potential.ResultsIn cultured prostate cancer LNCaP and PC-3 cells, R-568 treatment significantly reduced cellular survival in a dose- and time-dependent manner. R-568-induced cell death was an apoptotic event, as evidenced by caspase-3 processing and PARP cleavage, as well as JC-1 color change in mitochondria. Knocking down calcium sensing receptor (CaSR) significantly reduced R-568-induced cytotoxicity. Enforced expression of Bcl-xL gene abolished R-568-induced cell death, while loss of Bcl-xL expression led to increased cell death in R-568-treated LNCaP cells,.ConclusionTaken together, our data demonstrated that calcimimetic R-568 triggers an intrinsic mitochondria-related apoptotic pathway, which is dependent on the CaSR and is modulated by Bcl-xL anti-apoptotic pathway.
Highlights
Calcimimetic agents, like NPS R-568 (Cinacalcet HCl), is an allosteric agonist for parathyroid calcium-sensing receptor (CaSR) and was shown to lower circulating levels of parathyroid hormone (PTH) in patients with secondary hyperparathyroidism due to late-stage renal diseases [reviewed in [1,2]]
We surprisingly found for the first time that NPS R-568 induced apoptotic cell death, which is dependent on the CaSR and is modulated by anti-apoptotic Bcl-xL pathway
We evaluated R-568-induced effect on cellular survival in two prostate cancer cell lines, androgen receptorpositive LNCaP cells and androgen receptor-negative PC3 cells
Summary
Calcimimetic agents, like NPS R-568 (Cinacalcet HCl), is an allosteric agonist for parathyroid calcium-sensing receptor (CaSR) and was shown to lower circulating levels of parathyroid hormone (PTH) in patients with secondary hyperparathyroidism due to late-stage renal diseases [reviewed in [1,2]]. Clinical reports have shown that increased levels of serum PTH was frequently found in advanced prostate cancers [reviewed in ref. The biological effect of calcimimetic agents on prostate cancer cells has not been evaluated. In this study, we tested the biological effect of calcimimetic agent NPS R-568 on multiple prostate cancer cells. Increased serum level of parathyroid hormone (PTH) was found in metastatic prostate cancers. We investigated the effect of R-568 on cellular survival of prostate cancer cells
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