Role of protein S in castration-resistant prostate cancer-like cells

Abstract

Understanding how castration-resistant prostate cancer (CRPC) cells survive the androgen-deprivation condition is crucial for treatment of this advanced prostate cancer (PCa). Here, we reported for the first time the up-regulation of protein S (PROS), an anticoagulant plasma glycoprotein with multiple biological functions, in androgen-insensitive PCa cells and in experimentally induced castration-resistant PCa cells. Overexpression of exogenous PROS in LNCaP cells reduced androgen deprivation-induced apoptosis and enhanced anchorage-dependent clonogenic ability under androgen deprivation condition. Reciprocally, PROS1 knockdown inhibited cell invasiveness and migration, caused the growth inhibition of castration-resistant tumor xenograft under androgen-depleted conditions, and potentiated Taxol (a widely prescribed anti-neoplastic agent)-mediated cell death in PC3 cells. Furthermore, PROS overexpression significantly stimulated AKT activation but failed to evoke oxidative stress in LNCaP cells under normal condition, suggesting that the malignance-promoting effects of the above-mentioned pathway may occur in the order of oxidative stress/PROS/AKT. The potential mechanism may be due to control of oxidative stress-elicited activation of PI3K-AKT-mTOR pathway. Taken together, our gain-of-function, loss-of-function analyses suggest that PROS may facilitate cell proliferation and promote castration resistance in human castration-resistant PCa-like cells via its apoptosis-regulating property. Future study emphasizing on delineating how PROS regulate cellular processes controlling transformation during the development of castration resistance should open new doors for the development of novel therapeutic targets for CRPC.

Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy

“…Because no recombinant protein or other treatment other than low serum conditions was required for our observed in vitro effects, knockdown of MERTK may have caused epigenetic reprogramming of the cells as a result of chronic alterations in signaling from autocrine TAM receptor ligands. Prostate cancer cells are known to express MERTK ligands GAS6 and PROS1 (Protein S)(Jung, Decker et al 2016, Ning, Zhong et al 2016). The observed changes in histone H3 methylation also suggests that part of the effects of MERTK may be due to epigenetic reprogramming rather than through a more immediate response to ligands.…”

Synovial GATA1 mediates rheumatoid arthritis progression via transcriptional activation of NOS2 signaling

“…Synovial cells invasion assays were performed using Transwell chambers as described earlier . Briefly, serum‐starved MH7A cells were seeded at a density of 1 × 10 5 cells in the upper chamber, which was coated with Matrigel (Corning, Shanghai, China).…”

KLF14 potentiates oxidative adaptation via modulating HO-1 signaling in castrate-resistant prostate cancer

“…according to a previously validated protocol (Ning et al 2016). Interestingly, when LNCaP became castration resistant, as evidenced by the persistent high production of intracellular PSA and AR in the androgen-depleted medium, LNCaP-R cells showed an evoked level of KLF14 expression (Fig.…”

“…Other PCa cells were routinely cultured in RPMI-1640 medium supplemented with 10% FBS (GIBCO) in a 37°C, 5% CO 2 incubator. To establish castration-resistant LNCaP sublines (designated as LNCaP-R), LNCaP cells were maintained in media containing 10% charcoal-stripped FBS (FBS-CS, GIBCO) in the presence of 10 μM bicalutamide (Sigma-Aldrich) for 4 months, followed by measurement of intracellular prostate-specific antigen (PSA) and AR concentrations using commercially available ELSIA kits (Abcam), as described elsewhere (Ning et al 2016). To study the effects of oxidative stress on KLF14 expression, PCa cells were incubated with H 2 O 2 or diamide for various concentrations, in the presence or absence of 20 μmol/L diphenyleneiodonium chloride (Sigma-Aldrich) for different durations, as indicated.…”

“…This is referred to as castration-resistant prostate cancer (CRPC), an incurable stage in which ~90% of patients develop metastases with the highest mortality rate (Ferraldeschi et al 2015). Evidence from experimental and clinical studies have identified several potential mechanisms coexisting to confer CRPC, including deregulation of AR signaling (Zuo et al 2016), activation of PI3K/AKT/mTOR pathway (Zhang et al 2014b), perturbed lipid metabolism (Twiddy et al 2011, Qi et al 2013 and unbalanced oxidative stress (Shiota et al 2011, Ning et al 2016. In this scenario, continuous elucidation of the key molecules at different levels should strengthen our mechanistic understanding and provide valuable therapeutic guidance.…”