Polyamine Metabolism is Disturbed in Prostate Cancer

The recent development of the microarray technology has allowed analysis of expression levels of thousands of genes in one experiment. In a study to identify genes and pathways that are differentially expressed between androgen-dependent and androgen-independent cancer cells, Jenster et al. from the Department of Urology of the Erasmus MC in Rotterdam performed microarray experiments, using GeneChips that harbored approx 4000 known genes and 3000 expressed sequence tags. On each chip, two batches of RNA were compared by competitive hybridization with the glass-spotted complimentary DNAs. Comparing the expression of ODC, AdoMetDC, and SSATgenes in androgen-responsive LNCaP cells cultured in the absence or presence of 1 nM di-hydrotestosterone (DHT) for 16 h, it was observed that androgen stimulated the expression of these enzymes twofold to fourfold (Jenster et al., unpublished).

In a recent study, Rhodes et al. (22) conducted a meta-analysis of four independent microarray datasets to identify consistently significant candidate genes for prostate cancer. This study revealed a consistent and significant deregulation of polyamine biosynthesis in prostate cancer. Specifically, they found that enzymes linked to polyamine synthesis (aspartate transaminase, aminoacylase, ODC, and spermidine syn-thase) were overexpressed in prostate cancer, whereas ornithine aminotransferase was underexpressed. The net effect is an increased biosynthesis of polyamines. Biologically this makes sense because polyamines have been implicated in cancer cell proliferation, protection from apoptosis, and DNA-protein binding.

To investigate if ODC is involved in the cell kinetic behavior of human prostatic cancer cells, we examined ODC in cultured cells or xenografts of human prostatic cell lines. ODC protein was determined by Western blotting according to Schipper et al. (23). Activity of ODC was measured, as described earlier (24), in 48-h cultures and in xenografts of the prostatic cancer cell lines.

Results, as summarized in Table 1, indicate that ODC protein, as well as ODC activity, correlate with the growth rate of prostatic cancer cells (i.e., the amount of ODC protein is highest in the relatively fast growing tumor lines PC-324, PC-374, and PC-346). This is in agreement with studies in rat prostate-derived Dunning tumors reporting a substantially higher ODC activity in the faster growing sublines (25). Immunoblot analysis of human prostate cancer tissue specimens showed a significantly elevated ODC protein expression in the cancerous tissues as compared with the benign tissues (26). Moreover, studies on the expression levels of the ODC gene in a series of 23 human prostate cancers dissected from radical prostatectomy specimens revealed significantly higher ODC mRNA levels in tumors compared with the benign tissue (27). With a 5-yr follow-up study performed on the same cohort of patients, ODC gene profiling was proven to be an effective method for predicting the recurrence of prostate cancer, especially when combined with clinical-pathological parameters (28).

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