Mechanism of anti-proliferation effects of dehydroepiandrosterone on colon cancer

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Dehydroepiandrosterone (DHEA) is a naturally occurring steroid synthesized in the adrenal, brain and gastrointestinal tract. In vivo and in vitro administration of DHEA inhibits cancer proliferation. Two hypotheses have been proposed so far, 1) depletion of intracellular ribose due to inhibition of glucose-6-phosphate dehydrogenase (G6PD) activity ; and 2) inhibition of p21ras signal transduction pathway by dawn-regulation of HMG-CoA reductase (HMGR). To clarify the mechanism, the effects of DHEA and related steroids on the enzyme activities were studied in HepG2 cells. Cell growth was evaluated by MTT and bromodeoxyuridine incorporation assays. G6PD activity was measured by spectrophotometric assay, and the activities of HMGR and MAP kinase (MAPK), the final enzyme in the p21ras pathway, were determined by radioisotope incorporation methods. All steroids we tested had inhibitory effects on cell growth. Growth inhibition due to pregnenolone (PGN) and epiandrosterone (EA) was greater th … More an that caused by DHEA, while DHEA-sulfate, 7α-OH DHEA, 7β-OH DHEA and 7-keto DHEA had less inhibitory effects than DHEA.There was no significant correlation between growth inhibition and suppression of G6PD (r=0.552, NS) or HMGR (r=0.498, NS) activities. In contrast, highly significant positive correlation was observed between growth inhibition and suppression of MAPK activity (r=0.905, P<0.01).The same results were obtained when growth inhibition was evaluated by MTT assay. There was no significant correlation between inhibition of MTT assay and inhibition of G6PD activity (r=0.566, n=7, P=0.186) or inhibition of HMG-CoA reductase activity (r=0.442, n=7, P=0.321).In contrast, inhibition of MTT assay and inhibition of MAP-kinase was correlated significantly (r=0.807, n=7, P<0.05). These results demonstrate that not only DHEA but also all other steroids examined in this study have anti-proliferation effects on HepG2 cells. Inhibition of MAPK or some upstream molecules in the signal transduction appears to be more responsible for the anti-proliferation effects of these steroids than inhibition of G6PD or HMGR activity. Less