Abstract
BackgroundFor every six men, one will be diagnosed with prostate cancer (PCa) in their lifetime. Estrogen receptors (ERs) are known to play a role in prostate carcinogenesis. However, it is unclear whether the estrogenic effects are mediated by estrogen receptor Ī± (ERĪ±) or estrogen receptor Ī² (ERĪ²). Although it is speculated that ERĪ± is associated with harmful effects on PCa, the role of ERĪ² in PCa is still ill-defined. The cholesterol oxidized metabolite 27-hydroxycholesterol (27-OHC) has been found to bind to ERs and act as a selective ER modulator (SERM). Increased 27-OHC levels are found in individuals with hypercholesterolemia, a condition that is suggested to be a risk factor for PCa.MethodsIn the present study, we determined the extent to which 27-OHC causes deleterious effects in the non-tumorigenic RWPE-1, the low tumorigenic LNCaP, and the highly tumorigenic PC3 prostate cancer cells. We conducted cell metabolic activity and proliferation assays using MTS and CyQUANT dyes, protein expression analyses via immunoblots and gene expression analyses via RT-PCR. Additionally, immunocytochemistry and invasion assays were performed to analyze intracellular protein distribution and quantify transepithelial cell motility.ResultsWe found that incubation of LNCaP and PC3 cells with 27-OHC significantly increased cell proliferation. We also demonstrate that the ER inhibitor ICI 182,780 (fulvestrant) significantly reduced 27-OH-induced cell proliferation, indicating the involvement of ERs in proliferation. Interestingly, ERĪ² levels, and to a lesser extent ERĪ±, were significantly increased following incubation of PCa cells with 27-OHC. Furthermore, in the presence of the ERĪ² specific inhibitor, PHTPP, 27-OHC-induced proliferation is attenuated.ConclusionsAltogether, our results show for the first time that 27-OHC, through ER activation, triggers deleterious effect in prostate cancer cell lines. We propose that dysregulated levels of 27-OHC may trigger or exacerbate prostate cancer via acting on ERĪ².
Highlights
For every six men, one will be diagnosed with prostate cancer (PCa) in their lifetime
The cholesterol metabolite 27āOHC increases cell proliferation in PCa cells We have previously shown that 27-OHC stimulates cell proliferation in non-tumorigenic RWPE-1 cells [25]
Upon 27-OHC treatment, cell proliferation was increased by ~60% in LNCaP and ~30% in PC3 compared to their respective controls (Fig. 1a, b)
Summary
One will be diagnosed with prostate cancer (PCa) in their lifetime. 27-OHC levels are higher among those with hypercholesterolemia [17,18,19] and older men [16], both of which are at high risk of developing PCa. 27-OHC-induced ER activation has been shown to promote ER+ breast cancer growth and progression [18, 22,23,24]. Given that 27-OHC, at high levels, is associated with risk factors for PCa (i.e., hypercholesterolemia and aging) and that 27-OHC modulates ER signaling, a pathway that plays a role in PCa development and progression, it is essential to study the role of 27-OHC in the context of PCa. Further understanding of the role of 27-OHC in PCa may innovate alternative therapeutic avenues to those that are currently on the market
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