Abstract
Oxysterols are oxidation products of cholesterol. Cholestane-3β, 5α, 6β-triol (abbreviated as triol) is one of the most abundant and active oxysterols. Here, we report that triol exhibits anti-cancer activity against human prostate cancer cells. Treatment of cells with triol dose-dependently suppressed proliferation of LNCaP CDXR-3, DU-145, and PC-3 human prostate cancer cells and reduced colony formation in soft agar. Oral administration of triol at 20 mg/kg daily for three weeks significantly retarded the growth of PC-3 xenografts in nude mice. Flow cytometric analysis revealed that triol treatment at 10–40 µM caused G1 cell cycle arrest while the TUNEL assay indicated that triol treatment at 20–40 µM induced apoptosis in all three cell lines. Micro-Western Arrays and traditional Western blotting methods indicated that triol treatment resulted in reduced expression of Akt1, phospho-Akt Ser473, phospho-Akt Thr308, PDK1, c-Myc, and Skp2 protein levels as well as accumulation of the cell cycle inhibitor p27Kip. Triol treatment also resulted in reduced Akt1 protein expression in PC-3 xenografts. Overexpression of Skp2 in PC-3 cells partially rescued the growth inhibition caused by triol. Triol treatment suppressed migration and invasion of DU-145, PC-3, and CDXR-3 cells. The expression levels of proteins associated with epithelial-mesenchymal transition as well as focal adhesion kinase were affected by triol treatment in these cells. Triol treatment caused increased expression of E-cadherin protein levels but decreased expression of N-cadherin, vimentin, Slug, FAK, phospho-FAK Ser722, and phospho-FAK Tyr861 protein levels. Confocal laser microscopy revealed redistribution of β-actin and α-tubulin at the periphery of the CDXR-3 and DU-145 cells. Our observations suggest that triol may represent a promising therapeutic agent for advanced metastatic prostate cancer.
Highlights
Prostate cancer is the second most frequently diagnosed cancer of men and the fifth most common cancer overall in the world
We first sought to determine the effect of triol treatment on the viability and proliferation of three commonly used human prostate cancer cell lines (Fig. 1)
LNCaP CDXR-3 cells are androgen receptor (AR)-positive, relapsed, androgen-independent cells derived from parental AR-positive androgen-dependent LNCaP 104-S cells [27]
Summary
Prostate cancer is the second most frequently diagnosed cancer of men and the fifth most common cancer overall in the world. In Western countries, prostate cancer is the most common non-cutaneous carcinoma of men. Surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. Most prostate cancer patients receiving androgen ablation therapy will develop recurrent, castration-resistant tumors within 1–3 years after treatment. The median overall survival time is 1–2 years after cancer relapse [1,2]. No effective standard therapy exists for patients that relapse with advanced prostate cancer. Chemotherapy is often used to treat metastatic hormone-refractory prostate cancer [2,3]. New treatments for advanced prostate cancers are needed
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