Previous studies in several mammalian systems showed that the choice of chemical form and dose of selenium can strongly influence the observed biological effects.4,5
For example, p-XSC (1,4-phenylenebis(methylene)selenocyanate) significantly decreases the lung tumor incidence in mice exposed to NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), whereas SM does not.13
MSA and methylselnocysteine are equally effective for preventing DMBA (7,12-dimethylbenz(a)anthracene) induced rat mammary tumors, while SM is only half as effective.14,15
In LNCaP cells in vitro 10 μ
M MSA produces 50% inhibition in cell growth after 48 hours of treatment, while SM requires doses of 130 μ
M to achieve similar growth inhibition.6,7
Differences in the biological effects between SM and other selenium compounds have been attributed to differences in their conversion to methylselenol4,16
or to depletion of SM by its nonspecific incorporation into proteins.4
However, our finding of differences in global gene expression patterns induced by SM and MSA suggests that SM and other selenium compounds target different molecular and biological pathways in the cell.
Several studies, including ours, demonstrate that MSA and SM cause cell cycle arrest at different phases and our data show that they also change expression levels of cell cycle regulated genes differently. MSA decreases expression of transcripts from all phases of the cell cycle, suggesting that it causes LNCaP to exit the cell cycle rather than produce arrest at a specific phase.7
On the other hand, SM produces enrichment for up-regulated transcripts in the G1/S-phase and down-regulated transcripts in the G2/M phase, including several that are critical to G2/M progression, such as CDC25B and CDC25A. Consistent with gene expression changes, SM induced G2/M arrest of the cell cycle, whereas MSA resulted in an accumulation of cells at the G0/G1 phase. The modest increase in LNCaP in G2 (5% to 6%) after treatment with 10 to 100 μ
M SM was consistent with a previous study showing a 13% increase in cells in G2/M after treatment with 500 μ
Whether different selenium compounds can influence the androgen signaling pathway differently is less clear. Our studies showed that MSA as well as SM produced mixed effects on the transcript levels of androgen responsive genes since about half of the changes in expression suggested suppressed androgen signaling, while the remaining changes were consistent with stimulation. In addition, MSA affected the expression of many more AR and androgen responsive genes to a much greater degree than SM. In part it might have been due to the different effects of SM and MSA on AR levels. We previously reported that 10 μ
M MSA decreases transcript and protein levels of AR and PSA,7
possibly through suppressing AR binding to the androgen responsive element,17
while 10 μ
M SM has no effect on AR and PSA expression levels.18,19
However, 50 μ
M SM or longer exposure of LNCaP to SM at low concentrations (5 and 10 μ
M) also decreased AR mediated reporter gene expression.20
To our knowledge whether high SM levels could act on androgen responsive elements has not been tested.
The different effects of SM and MSA on the transcriptional programs of PC cells might have important implications in the interpretation and outcome of PC intervention trials using selenium. It is possible that the mixture of organic selenium compounds found in the diet and in selenized yeast, as in the NPC intervention trial, could show different biological effects than pure SM. If SELECT is a negative trial, possible interpretations could be that selenium compounds do not protect against PC or selenium compounds other than SM are important for cancer prevention. Improved understanding of the mechanisms of action of selenium for PC prevention and the development of bio-markers germane to the pathways involved could clarify whether the differences in action observed in vitro are relevant in vivo.