Regulation of transforming growth factor gene expression in human endometrial adenocarcinoma cells.
We have examined the effects of medroxyprogesterone acetate (MPA) and 4-hydroxytamoxifen (OH-TAM) on the cell proliferation and the expression of TGF-alpha and TGF-beta genes in Ishikawa cells and HEC-50 human endometrial adenocarcinoma cells. The effects of exogenous TGF-alpha, TGF-beta and anti-EGF receptor monoclonal antibody on cell proliferation were also determined. Antisense oligonucleotides were used to determine the effects of endogenous expression of TGF-alpha and TGF-beta. In both cell lines, MPA resulted in a time and dose-dependent inhibition of cell proliferation whereas OH-TAM had no effect on HEC-50 cell proliferation. The relative abundance of TGF-alpha mRNA was significantly reduced by MPA in Ishikawa cells but not in HEC-50 cells. In Ishikawa cells, a reduction in TGF-alpha mRNA abundance was observed with OH-TAM under conditions where both inhibition and stimulation of cell proliferation were demonstrated. Anti-EGF receptor monoclonal antibody inhibited Ishikawa cell growth but had little effect on HEC-50 cell proliferation. Exogenous TGF-alpha stimulated proliferation of both cell lines whereas exogenous TGF-beta inhibited proliferation of Ishikawa cells but stimulated proliferation of HEC-50 cells. Antisense oligonucleotides to TGF-beta inhibited proliferation of HEC-50 cells. From these data we conclude that the antiproliferative effects of progestins and OH-TAM on endometrial cancer cells appear to be mediated by different mechanisms.
Murphy
L J
LJ
Department of Internal Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Gong
Y
Y
Murphy
L C
LC
D000230:Adenocarcinoma / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016889:Endometrial Neoplasms / Q000235:genetics*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008525:Medroxyprogesterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D017258:Medroxyprogesterone Acetate; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D013256:Steroids / Q000494:pharmacology; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000235:genetics* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D016376:Oligonucleotides, Antisense; D013256:Steroids; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; C016601:afimoxifene; D017258:Medroxyprogesterone Acetate; D008525:Medroxyprogesterone