Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth-suppressor gene

• Published in: Cancer epidemiology Vol. 34; no. 4; pp. 461 - 471
• Main Authors: Ifere, Godwin O, Equan, Anita, Gordon, Kereen, Nagappan, Peri, Igietseme, Joseph U, Ananaba, Godwin A
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.08.2010; Elsevier Limited
• Subjects: Apoptosis; Apoptosis - drug effects; Biomarkers; Blotting, Western; Cancer; Caveolin 1 - genetics; Caveolin 1 - metabolism; Caveolin- 1; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Proliferation - drug effects; Chemoprevention; Cholesterol; Cholesterol - pharmacology; Conflicts of interest; Epidemiology; Flow Cytometry; Gene Expression Regulation, Neoplastic - drug effects; Growth-suppressor; Hematology, Oncology and Palliative Medicine; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; NDRG1; Phytosterols; Phytosterols - pharmacology; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sterols; Tumor Cells, Cultured; Sterols; Growth-suppressor; Caveolin- 1; Chemoprevention; Phytosterols; Biomarkers; Prostate cancer; NDRG1; Cholesterol; Apoptosis
• ISSN: 1877-7821; 1877-783X
• DOI: 10.1016/j.canep.2010.04.009

Abstract Background: The purpose of our study was to show the distinction between the apoptotic and anti-proliferative signaling of phytosterols and cholesterol-enrichment in prostate cancer cell lines, mediated by the differential transcription of caveolin-1, and N - myc downstream - regulated gene 1 ( NDRG1 ), a pro-apoptotic androgen-regulated tumor suppressor. Methods: PC-3 and DU145 cells were treated with sterols (cholesterol and phytosterols) for 72 h, followed by trypan blue dye-exclusion measurement of necrosis and cell growth measured with a Coulter counter. Sterol induction of cell growth-suppressor gene expression was evaluated by mRNA transcription using RT-PCR, while cell cycle analysis was performed by FACS analysis. Altered expression of Ndrg1 protein was confirmed by Western blot analysis. Apoptosis was evaluated by real time RT-PCR amplification of P53 , Bcl - 2 gene and its related pro- and anti-apoptotic family members. Results: Physiological doses (16 μM) of cholesterol and phytosterols were not cytotoxic in these cells. Cholesterol-enrichment promoted cell growth ( P < 0.05), while phytosterols significantly induced growth-suppression ( P < 0.05) and apoptosis. Cell cycle analysis showed that contrary to cholesterol, phytosterols decreased mitotic subpopulations. We demonstrated for the first time that cholesterols concertedly attenuated the expression of caveolin - 1 ( cav - 1 ) and NDRG1 genes in both prostate cancer cell lines. Phytosterols had the opposite effect by inducing overexpression of cav - 1 , a known mediator of androgen-dependent signals that presumably control cell growth or apoptosis. Conclusions: Cholesterol and phytosterol treatment differentially regulated the growth of prostate cancer cells and the expression of p53 and cav - 1 , a gene that regulates androgen-regulated signals. These sterols also differentially regulated cell cycle arrest, downstream pro-apoptotic androgen-regulated tumor suppressor, NDRG1 suggesting that cav - 1 may mediate pro-apoptotic NDRG1 signals. Elucidation of the mechanism for sterol modulation of growth and apoptosis signaling may reveal potential targets for cancer prevention and/or chemotherapeutic intervention. Sterol regulation of NDRG1 transcription suggests its potential as biomarker for prediction of neoplasms that would be responsive to chemoprevention by phytosterols.