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The Regulation of Apoptosis by Activin and Transforming Growth Factor-ß in Early Neoplastic and Tumorigenic Ovarian Surface Epithelium¹

Department of Obstetrics and Gynecology, British Columbia Women’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5

Address all correspondence and requests for reprints to: Peter C. K. Leung, Ph.D., Department of Obstetrics and Gynecology, University of British Columbia, 2H30-4490 Oak Street, British Columbia Women’s Hospital, Vancouver, British Columbia, Canada V6H 3V5. E-mail: peleung{at}interchange.ubc.ca

Most ovarian neoplasms arise from the ovarian surface epithelium (OSE), and multiple growth factors have been implicated to influence the transformation from OSE. The present study was performed to investigate the role of activin and transforming growth factor-ß (TGFß) in normal and neoplastic OSE cells. An immortalized OSE cell line (IOSE-29) was generated from normal OSE by transfecting simian virus 40 large T antigen and was rendered tumorigenic after subsequent transfection with the E-cadherin gene (IOSE-29EC). The activin/inhibin subunits and activin receptors were expressed at both messenger ribonucleic acids and protein levels in these cells, suggesting that activin may have an autocrine role in neoplastic OSE cells. Treatments with activin (1–100 ng/mL) resulted in a significant decrease in cell proliferation in both IOSE-29 and IOSE-29EC cells, although we have shown that it stimulated the growth of ovarian cancer cells and had no effect on normal OSE. This inhibitory effect was attenuated with cotreatment with follistatin. Treatment with TGFß (0.1–10 ng/mL) also significantly decreased the proliferation of normal, IOSE-29, and IOSE-29EC cells in a dose-dependent manner. In addition, treatments with both activin and TGFß resulted in an increase in DNA fragmentation in IOSE-29EC cells in a dose-dependent manner. This apoptotic effect of activin was attenuated by cotreatment with follistatin. Treatment with TGFß (1 and 10 ng/mL) resulted in a significant decrease in Bcl-2 protein (up to 50%) in IOSE-29EC, whereas no difference was observed in Bax protein levels. Therefore, down-regulated Bcl-2 by TGFß may eventually induce apoptosis in IOSE-29EC cells. In contrast, no difference was observed in Bax and Bcl-2 protein expression after treatment with activin. In conclusion, the present study indicates that activin and TGFß inhibited growth and induced apoptosis in early neoplastic (IOSE-29) and tumorigenic OSE (IOSE-29EC) cells. Furthermore, antiapoptotic Bcl-2 protein was down-regulated by TGFß, whereas no difference was produced in Bax protein by activin or TGFß treatment or in Bcl-2 protein by activin. These results suggest that activin and TGFß may play a role in growth inhibition and induction of apoptosis in early neoplastic and tumorigenic stage of ovarian cancer.

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