The cholesterol metabolite 27-hydroxycholesterol stimulates cell proliferation via ERβ in prostate cancer cells

Shaneabbas Raza, Megan Meyer, Casey Goodyear, Kimberly D.P. Hammer, Bin Guo, Othman Ghribi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: For 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 α (ERα) or estrogen receptor β (ERβ). Although it is speculated that ERα is associated with harmful effects on PCa, the role of ERβ 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. Methods: In 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. Results: We 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, ERβ levels, and to a lesser extent ERα, were significantly increased following incubation of PCa cells with 27-OHC. Furthermore, in the presence of the ERβ specific inhibitor, PHTPP, 27-OHC-induced proliferation is attenuated. Conclusions: Altogether, 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 ERβ.

Original languageEnglish (US)
Article number52
JournalCancer Cell International
Volume17
Issue number1
DOIs
StatePublished - May 11 2017

Fingerprint

Estrogen Receptors
Prostatic Neoplasms
Cholesterol
Cell Proliferation
27-hydroxycholesterol
Selective Estrogen Receptor Modulators
Hypercholesterolemia
Cell Movement
Prostate
Estrogens
Carcinogenesis
Proteins
Coloring Agents
Immunohistochemistry
Gene Expression
Cell Line
Polymerase Chain Reaction

Keywords

  • 27-Hydroxycholesterol
  • Estrogen receptor
  • Hypercholesterolemia
  • Proliferation
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

The cholesterol metabolite 27-hydroxycholesterol stimulates cell proliferation via ERβ in prostate cancer cells. / Raza, Shaneabbas; Meyer, Megan; Goodyear, Casey; Hammer, Kimberly D.P.; Guo, Bin; Ghribi, Othman.

In: Cancer Cell International, Vol. 17, No. 1, 52, 11.05.2017.

Research output: Contribution to journalArticle

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AU - Meyer, Megan

AU - Goodyear, Casey

AU - Hammer, Kimberly D.P.

AU - Guo, Bin

AU - Ghribi, Othman

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N2 - Background: For 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 α (ERα) or estrogen receptor β (ERβ). Although it is speculated that ERα is associated with harmful effects on PCa, the role of ERβ 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. Methods: In 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. Results: We 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, ERβ levels, and to a lesser extent ERα, were significantly increased following incubation of PCa cells with 27-OHC. Furthermore, in the presence of the ERβ specific inhibitor, PHTPP, 27-OHC-induced proliferation is attenuated. Conclusions: Altogether, 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 ERβ.

AB - Background: For 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 α (ERα) or estrogen receptor β (ERβ). Although it is speculated that ERα is associated with harmful effects on PCa, the role of ERβ 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. Methods: In 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. Results: We 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, ERβ levels, and to a lesser extent ERα, were significantly increased following incubation of PCa cells with 27-OHC. Furthermore, in the presence of the ERβ specific inhibitor, PHTPP, 27-OHC-induced proliferation is attenuated. Conclusions: Altogether, 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 ERβ.

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