The Journal of Nutritional Biochemistry
Volume 20, Issue 12 , Pages 1000-1012, December 2009

Profiling of zinc-altered gene expression in human prostate normal vs. cancer cells: a time course study☆☆☆

  • Shu-fei Lin

      Affiliations

    • Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland at Baltimore, Baltimore, MD 21201, USA
    • ,
  • Hua Wei

      Affiliations

    • Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland at Baltimore, Baltimore, MD 21201, USA
    • ,
  • Dennis Maeder

      Affiliations

    • University of Maryland Biotechnology Institute, Baltimore, MD 21201, USA
    • ,
  • Renty B. Franklin

      Affiliations

    • Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland at Baltimore, Baltimore, MD 21201, USA
    • Greenebaum Cancer Center, University of Maryland at Baltimore, Baltimore, MD 21201, USA
    • ,
  • Pei Feng

      Affiliations

    • Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland at Baltimore, Baltimore, MD 21201, USA
    • Greenebaum Cancer Center, University of Maryland at Baltimore, Baltimore, MD 21201, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 410 706 7340; fax: +1 410 706 0865.

Received 20 May 2008; received in revised form 3 September 2008; accepted 9 September 2008. published online 15 December 2008.

Abstract 

We have demonstrated that zinc exposure induces apoptosis in human prostate cancer cells (PC-3) and benign hyperplasia cells (BPH), but not in normal prostate cells (HPR-1). However, the mechanisms underlying the effects of zinc on prostate cancer cell growth and zinc homeostasis remain unclear.

To explore the zinc effect on gene expression profiles in normal (HPR-1) and malignant prostate cells (PC-3), we conducted a time course study of Zn treatment with microarray analysis. Microarray data were evaluated and profiled using computational approach for the primary and secondary data analyses. Final analyses were focused on the genes (1) highly sensitive to zinc; (2) associated with zinc homeostasis, i.e., metallothioneins (MTs), solute zinc carriers (ZIPs) and zinc exporters (ZnTs); (3) relevant to several oncogenic pathways. Zinc-mediated mRNA levels of MT isotypes were further validated by semi-quantitative RT-PCR.

Results showed that zinc effect on genome-wide expression patterns was cell-type specific, and zinc appeared to have mainly down-regulatory effects on thousands of genes (1953 in HPR-1; 3534 in PC-3) with a threshold of ±2.5-fold, while fewer genes were up-regulated (872 in HPR-1; 571 in PC-3). The patterns of zinc effect on functional MT genes' expression provided evidence for the cell type-dependent zinc accumulation and zinc-induced apoptosis in prostate cells. In PC-3 cells, zinc significantly up-regulated the expression of MT-1 isotypes MT-1J and MT-1M, denoted previously as “nonfunctional” MT genes, and now a depictive molecular structure of MT-1J was proposed. Examination of genes involved in oncogenic pathways indicated that certain genes, e.g., Fos, Akt1, Jak3 and PI3K, were highly regulated by zinc with cell-type specificity.

This work provided an extensive database on zinc-related prostate cancer research. The strategy of data analysis was devoted to finding genes highly sensitive to Zn, and the genes associated with zinc accumulation and zinc-induced apoptosis. The results indicate that zinc regulation of gene expression is cell-type specific, and MT genes play important roles in prostate malignancy.

Keywords: Microarray, Zinc, Prostate malignant cells, Gene isoform, Metallothionein, Zinc transporter

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☆ Authors' contributions: Shu-fei Lin performed the microarray study, RT-PCR, data analysis, related statistical analyses and participated in manuscript preparation. Hua Wei performed RT-PCR, contributed and participated in producing the tables and figures. Dennis Maeder predicted the protein structure for MT-1J. Renty B. Franklin participated in the discussions and manuscript preparation. Pei Feng conceived the study, responded to its design, coordination, data analysis and the completion of the manuscript. All authors read and approved the final manuscript.

☆☆ This study was supported by funding from NIH/National Cancer Institute grant R01-116815 to P. Feng.

PII: S0955-2863(08)00213-1

doi:10.1016/j.jnutbio.2008.09.004

The Journal of Nutritional Biochemistry
Volume 20, Issue 12 , Pages 1000-1012, December 2009

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