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Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by
Yan Dong1, Haitao Zhang, Lesleyann Hawthorn
1Department of Cancer Prevention, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Abstract:
Despite the growing interest in selenium intervention of prostate cancer in humans, scanty information is currently available on the molecular mechanism of selenium action. Our past research indicated that methylseleninic acid (MSA) is an excellent reagent for investigating the anticancer effect of selenium in vitro. The present study was designed to examine the cellular and molecular effects of MSA in PC-3 human prostate cancer cells. After exposure to physiological concentrations of MSA, these cells exhibited a dose- and time-dependent inhibition of growth. MSA retarded cell cycle progression at multiple transition points without changing the proportion of cells in different phases of the cell cycle. Flow cytometric analysis of annexin V- and propidium iodide-labeled cells showed a marked induction of apoptosis by MSA. Array analysis with the Affymetrix human genome U95A chip was then applied to profile the gene expression changes that might mediate the effects of selenium. Gene profiling was done in a time course experiment (at 12, 24, 36, and 48 h) using synchronized cells. A large number of potential selenium-responsive genes with diverse biological functions were identified. These genes fell into 12 clusters of distinct kinetics pattern of modulation by MSA. The expression changes of 10 genes known to be critically involved in cell cycle regulation were selected for verification by Western analysis to determine the reliability of the array data. An agreement rate of 70% was obtained based on these confirmation experiments. The array data enabled us to focus on the role of potential key genes (e.g., GADD153, CHK2, p21(WAF1), cyclin A, CDK1, and DHFR) that might be targets of MSA in impeding cell cycle progression. The data also provide valuable insights into novel biological effects of selenium, such as inhibition of cell invasion, DNA repair, and stimulation of transforming growth factor beta signaling. The present study demonstrates the utility of a genome-wide analysis to elucidate the mechanism of selenium chemoprevention.
Insights
Methylseleninic acid (MSA) inhibits prostate cancer cell growth and induces apoptosis. Genome-wide analysis identified key genes and pathways involved in selenium
Area of Science:
- Oncology
- Molecular Biology
- Nutritional Science
Background:
- Prostate cancer remains a significant health concern with growing interest in selenium's chemopreventive potential.
- The molecular mechanisms underlying selenium's anticancer effects, particularly its intervention in prostate cancer, are not fully understood.
- Methylseleninic acid (MSA) has been identified as a promising selenium compound for in vitro investigation of anticancer mechanisms.
Purpose of the Study:
- To investigate the cellular and molecular effects of methylseleninic acid (MSA) on PC-3 human prostate cancer cells.
- To elucidate the gene expression changes induced by MSA using genome-wide array analysis.
- To identify potential molecular targets and pathways mediating selenium's chemopreventive effects in prostate cancer.
Main Methods:
- PC-3 human prostate cancer cells were treated with physiological concentrations of MSA.
- Cellular effects including growth inhibition, cell cycle progression, and apoptosis were analyzed using flow cytometry.
- Genome-wide gene expression profiling was performed using Affymetrix arrays in a time-course experiment.
Main Results:
- MSA demonstrated dose- and time-dependent inhibition of PC-3 cell growth and induced apoptosis.
- MSA treatment altered cell cycle progression without significantly changing the proportion of cells in different phases.
- Genome-wide analysis identified numerous selenium-responsive genes, revealing potential roles in cell cycle regulation, invasion, DNA repair, and TGF-beta signaling.
Conclusions:
- Methylseleninic acid exhibits significant anticancer effects on prostate cancer cells by inhibiting growth and inducing apoptosis.
- Genome-wide gene expression profiling is a valuable tool for elucidating the molecular mechanisms of selenium chemoprevention.
- The study identified key genes and pathways, such as GADD153, CHK2, and p21(WAF1), as potential targets of MSA in prostate cancer.