| Summary: | 碩士 === 長庚大學 === 醫學生物技術研究所 === 92 === Dehydroepiandrosterone (DHEA) is a steroid hormone secreted abundantly by the adrenal glands and it is a precursor of sex steroid biosynthesis. Previous studies indicate that it has anti-proliferative actions on cultured cells but the mechanism is unclear. In the present study, we investigated whether DHEA has anti-proliferative effect on human foreskin fibroblast (HFF) and if so, whether such growth inhibitory effect is mediated by the inhibition of glucose-6-phosphate dehydrogenase (G6PD) or HMG-CoA reductase (HMGR) enzyme. Both of these enzymes had been previously reported to be the underlying cause of growth inhibition induced by DHEA. As measured by trypan blue counting, the cell number decreased by 55 % after 96 hrs’ incubation with DHEA. Similarly, an increase in the percentage of cells in G1 phase and a concomitant decrease in that of S phase cells by cell cycle analysis indicate the DHEA induces growth arrest of HFF cells. In addition, treatment with DHEA can induce a rapid senescence-like state characterized by an enlarged cellular morphology and positive beta-galactosidase staining. However, the G6PD activity of cells incubated with DHEA for 96 hrs was 130% of control. Likewise, HMGR activity of cells incubated with DHEA for 48 hrs was 232% of control. Mechanistically, the mitochondrial membrane potential (MMP) down to 50% of untreated control and cellular ATP level decreased by 30% after DHEA treatment for 96 hrs. Moreover, a transcriptional coactivator, PGC-1alpha was also dose- and time-dependently induced by DHEA. In particular, the growth inhibition by DHEA was ameliorated by glucose addition during incubation, but not by the addition of pyruvate. Taken together, these results show that DHEA-induced mitochondrial dysfunction can lead to growth arrest and PGC-1alpha activation may be involved in this process.
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