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Regulation of apoptosis in normal and malignant ovarian epithelial cells by transforming growth factor beta
L J Havrilesky1, J A Hurteau, R S Whitaker
1Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710.
Abstract:
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.
Insights
Transforming growth factor beta (TGF-beta) inhibits normal ovarian cell proliferation but induces apoptosis in some ovarian cancers. Malignant cells appear more susceptible to TGF-beta-induced apoptosis than normal cells.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Transforming growth factor beta (TGF-beta) is known to inhibit normal human ovarian epithelial cell proliferation.
- While TGF-beta affects few immortalized ovarian cancer cell lines, it inhibits the proliferation of most primary epithelial ovarian cancers.
Purpose of the Study:
- To investigate whether TGF-beta induces apoptosis in normal and malignant ovarian epithelial cells.
- To compare the apoptotic response of normal ovarian cells, immortalized cancer cell lines, and primary ovarian cancers to TGF-beta.
Main Methods:
- Treatment of normal ovarian epithelial cells, immortalized ovarian cancer cell lines (including OVCA 420), and primary ovarian cancers with TGF-beta.
- Assessment of cell proliferation via [3H]thymidine incorporation.
- Evaluation of apoptosis induction through DNA fragmentation assays.
- Analysis of p53 status in relation to TGF-beta-induced apoptosis.
Main Results:
- TGF-beta inhibited proliferation in all normal ovarian epithelial cells but did not induce apoptosis.
- TGF-beta markedly inhibited growth and induced apoptosis in the OVCA 420 cell line, with induction being time and concentration-dependent.
- TGF-beta inhibited proliferation in all primary ovarian cancers, with apoptosis observed in 30% of cases; p53 status did not correlate with apoptosis induction.
Conclusions:
- TGF-beta inhibits proliferation but not apoptosis in normal ovarian epithelial cells.
- Some ovarian cancers exhibit TGF-beta-induced apoptosis, suggesting malignant cells are more susceptible than normal counterparts.
- These findings support the hypothesis of increased apoptotic susceptibility in malignant ovarian cells compared to normal cells.