Characterizing the Role of Calcium Sensing Receptor in the Progression of Obesity-Mediated Aggressive Prostate Cancer Phenotype.

Obesity increases the risk of advanced prostate cancer (PCa). The calcium sensing receptor (CaSR) has been shown to be responsive to obesity-mediated cytokines and is upregulated in metastatic PCa. This study used a novel in vitro approach, involving the exposure of PCa cells to sera, from obese or normal weight males, and to CaSR inhibitor NPS-2143. Cell viability was determined using MTT assay. MMP-9 activity and invasion were assessed using zymography and invasion chambers, respectively. Microscopy was used to visualize EMT proteins. qRT-PCR and immunoblot analysis were used to quantify changes in genes and proteins important for tumorigenesis. Exposure to obese sera increased the proliferation, and the invasive capacity of PCa cells and de-localized epithelial-mesenchymal transition markers, which were attenuated with CaSR inhibition. Exposure to obese sera upregulated mRNA expression of PTHrP and protein expression of COX-2, IL-6, and CaSR. Inhibition of CaSR downregulated the mRNA expression of PTHrP and RANK, and protein expression of pERK and TNF-α. Obesity was shown to increase invasion and upregulate the expression of genes and proteins involved in PCa tumorigenesis. CaSR inhibition downregulated the expression of several of these factors. Thus, CaSR is a potentially important protein to target in obesity-mediated PCa progression.

Silibinin Differentially Decreases the Aggressive Cancer Phenotype in an In Vitro Model of Obesity and Prostate Cancer.

Aim: Obesity increases the risk for aggressive and fatal prostate cancer (PCa). The bioactive compound silibinin has been researched for its chemopreventative properties and may benefit obese or overweight individuals with PCa.Methods: This study used an in vitro model of obesity exposing prostate cancer cells to sera from obese, overweight, or normal weight males with or without the addition of silibinin. Molecular activity was assayed as well as the phenotype of PCa cells with various treatments.Results: Obesity increased the expression of proliferative signaling including COX-2, IL-6, AKT, ERK, and AR, which was attenuated with silibinin. Cell growth, and invasive capacity of prostate cancer cells was increased with obese and overweight sera, and silibinin was able to mitigate this affect. However, there are limitations to this study in that an in vivo model was not used to validate these in vitro results nor a co-culture model, which may better recapitulate the tumor microenvironment.Conclusions: Silibinin may be a safe intervention for those with or at risk for prostate cancer, and it may be the most beneficial for obese or overweight males.