Comparison of PDE expression profiles of human prostate and prostate cancer cell lines and the effect of PDE inhibitors on cell proliferation

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It is well known that elevation of intracellular cyclic nucleotide levels inhibit cell proliferation. Non-selective phosphodiesterase (PDE) inhibitors have been shown to attenuate cancer cell growth. Due to the side effects, they cannot be used clinically. Efforts to search for specific PDE inhibitors that could accomplish the same goal continue. Here we report that normal human prostate contains PDE2, 3, 4, and 5, based on enzyme activities. Selective inhibitors for these PDEs and papaverine, a non-selective inhibitor, were assessed for their ability to inhibit proliferation of three prostate cancer lines, PC3, DU145, and LNCaP. Papaverine induced dose-dependent inhibition of proliferation after one, three, and six-day treatments. EHNA, a PDE2 selective inhibitor, decreased cell proliferation after treatments for three and six days. The temporal increases in cAMP and cGMP concentrations in PC3 and DU145 cells correlated well with the inhibition of proliferation. Selective inhibitors for PDE3, 4, or 5 failed to significantly increase cyclic nucleotide levels or attenuate cell growth in any of the three cell lines. To determine whether PDE2 was the major PDE in the cell lines, real-time RT-PCR was carried out for all the cloned PDEs except PDE6. At mRNA level, PDE2 expression was lower than several other PDEs in all three cell lines. Its expression was also significantly lower in the cell lines than in normal human prostate. Our results showed that papaverine and EHNA both inhibited the proliferation of the three prostate cell lines. PDE2 is not among the most highly expressed PDEs in the cell lines. The PDE expression profiles are different among the prostate cell lines and the normal prostate.