Regulation of apoptosis in normal and malignant ovarian epithelial cells by transforming growth factor beta.
Previously, we found that transforming growth factor beta (TGF-beta) inhibits proliferation of normal human ovarian epithelial cells. In addition, although only 1 of 5 immortalized ovarian cancer cell lines was inhibited, TGF-beta inhibited proliferation of 19 of 20 primary epithelial ovarian cancers. In this study, we examined whether TGF-beta induces apoptosis in normal and malignant ovarian epithelial cells. Among 5 immortalized cell lines, only OVCA 420 is markedly growth inhibited by TGF-beta, and this was the only cell line in which TGF-beta elicited DNA fragmentation characteristic of apoptosis. Induction of apoptosis in OVCA 420 was time and concentration dependent and could be partially inhibited by concurrent treatment with an anti-TGF-beta mAb. Although apoptosis was not seen in normal ovarian epithelial cells (n = 7), [3H]thymidine incorporation was inhibited in all cases [mean = 61.2 +/- 7.2% (SD) of untreated control; P < 0.01]. Similarly, TGF-beta inhibited [3H]thymidine incorporation in all 10 primary ovarian cancers (mean = 40.4 +/- 7.1% of control; P < 0.01), but only 3 of 10 (30%) were found to undergo apoptosis when treated with TGF-beta. There was no relationship between p53 status of the ovarian cancers and the ability of TGF-beta to elicit apoptosis. In conclusion, TGF-beta inhibits proliferation but does not induce apoptosis in normal human ovarian epithelial cells. In contrast, some ovarian cancers that are growth inhibited by TGF-beta also undergo apoptosis. These data are consistent with the hypothesis that malignant cells are more susceptible to apoptosis than their normal nontransformed counterparts.
Havrilesky
L J
LJ
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710.
Hurteau
J A
JA
Whitaker
R S
RS
Elbendary
A
A
Wu
S
S
Rodriguez
G C
GC
Bast
R C
RC
Berchuck
A
A
D000906:Antibodies; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D004847:Epithelial Cells; D004848:Epithelium / Q000473:pathology; D005260:Female; D016158:Genes, p53; D006801:Humans; D015151:Immunoblotting; D007633:Keratins / Q000276:immunology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D010053:Ovary / Q000166:cytology* / Q000502:physiology*; D012016:Reference Values; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000906:Antibodies; D016212:Transforming Growth Factor beta; D007633:Keratins