The androgen receptor as a potential regulator of prostate cancer contractility.

Abstract

Prostate cancer (PCa) is a common health hazard for men that displays androgen-dependent growth at early stages through signalling mediated by the Androgen Receptor (AR). This has inspired androgen deprivation therapy (ADT) to be the gold standard treatment; however, in later stages, PCa displays a transition to androgen-independence and loss of AR, accompanied by a drastic increase in invasiveness. Critically, both the loss of AR and ADT have been shown to induce PCa invasiveness by promoting the epithelial-to-mesenchymal transition (EMT) which has been associated with biophysical changes in other cell models. Indeed, during metastasis cancers cells change their biophysical properties (reduced cell stiffness, increased contractility) facilitating migration through crowded microenvironments. Given AR's essential role in mediating PCa progression, we suspect that AR signalling may also regulate mechanical transitions required for PC metastasis and directed cell migration. In this study we characterize PCa biophysics in response to changes in AR signalling and expression. First, we applied Traction Force Microscopy on the metastatic PCa cell line LNCaP (AR-positive) to quantify contractile changes from androgen deprivation and supplementation, observing a non-monotonic contractile response with increasing androgen dose. These results suggest that the androgen-induced biophysical response shifts depending on the androgen availability, a finding consistent with past reports demonstrating that distinct pathways depend on both androgen concentration and AR expression. Regarding the latter, we then evaluated how AR expression and activity (nuclear localization) affects PCa biophysics by quantifying the contractility of highly metastatic PC3 cells with and without AR expression under varying androgen concentrations. We find that cell contractility is positively correlated with AR nuclear localization in androgen-containing media, yet negatively correlated in androgen-deprived media. These results complement emerging trends suggesting AR may have an important mechanobiological role in PCa migration and metastasis.