title: Apoptosis and inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway in the anti-proliferative actions of dehydroepiandrosterone.
abstract: BACKGROUND
  Dehydroepiandrosterone (DHEA) is an endogenous steroid that is synthesized mainly in the adrenal cortex; it is found in plasma as the sulfate-conjugated form (DHEA-S). Pharmacological doses of DHEA exhibit anti-proliferative effects on malignant cell lines and some tumors in experimental animals. The purpose of this study was to evaluate the effect of these steroids on proliferation in human cancer cell lines.
  
  
  METHODS
  HepG2 and HT-29 cell lines were treated with DHEA or DHEA-S at 0-200 microM for 24 h or at 100 microM for 8-72 h, and then effects on cell growth, and the cell cycle and on apoptosis, were evaluated by 3-[4,5-dimethylthiazol]-2yl-2,5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry, respectively. Also, the effect of DHEA on phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in HepG2 cells by Western blotting.
  
  
  RESULTS
  The growth of HepG2 and HT-29 cells was significantly inhibited by DHEA, in a dose- and time-dependent manner. This inhibition was greater in HepG2 than in HT-29 cells. Accumulation at G0/G1 phase in both cell lines was observed with DHEA treatment. However, apoptosis increased significantly only in HepG2 cells. In contrast, DHEA-S exhibited much weaker growth inhibitory and cytostatic effects on both cell lines, and apoptosis was not detected. In HepG2 cells treated with DHEA, apoptosis was associated with markedly reduced Akt phosphorylation (Thr308 and Ser473), suggesting that DHEA inhibited the PI3K/Akt signaling to induce apoptosis in these cells.
  
  
  CONCLUSIONS
  These results suggest that the induction of apoptosis through the inhibition of the PI3K/Akt signaling pathway is one of the anti-proliferative mechanisms of DHEA in certain tumors, but that DHEA also promotes cell-cycle arrest without the induction of apoptosis.
authors.affiliation: Division of Gastroenterology and Hepatology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences and University Hospital, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Jiang
authors.forename: Teruo
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirayama
authors.forename: Shigemasa
authors.initials: S
authors.lastname: Yoshida
authors.forename: Naomi
authors.initials: N
authors.lastname: Tanaka
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzaki
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D003687:Dehydroepiandrosterone; D019869:Phosphatidylinositol 3-Kinases