The regulation of apoptosis by activin and transforming growth factor-betain early neoplastic and tumorigenic ovarian surface epithelium

Most ovarian neoplasms arise from the ovarian surface epithelium (OSE), and multiple growth factors have been implicated to influence the transformati on from OSE. The present study was performed to investigate the role of act ivin and transforming growth factor-beta (TGF beta) in normal and neoplasti c OSE cells. An immortalized OSE cell line (IOSE-29) was generated from nor mal OSE by transfecting simian virus 40 large T antigen and was rendered tu morigenic after subsequent transfection with the E-cadherin gene (IOSE-29EC ). The activin/inhibin subunits and activin receptors were expressed at bot h messenger ribonucleic acids and protein levels in these cells, suggesting that activin may have an autocrine role in neoplastic OSE cells. Treatment s with activin (1-100 ng/mL) resulted in a significant decrease in cell pro liferation 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 norm al OSE. This inhibitory effect was attenuated with cotreatment with follist atin. Treatment with TGF beta (0.1-10 ng/mL) also significantly decreased t he proliferation of normal, IOSE-29, and IOSE-29EC cells in a dose-dependen t manner. In addition, treatments with both activin and TGF beta resulted i n an increase in DNA fragmentation in IOSE-29EC cells in a dose-dependent m anner. This apoptotic effect of activin was attenuated by cotreatment with follistatin. Treatment with TGF beta (1 and 10 ng/mL) resulted in a signifi cant decrease in Bcl-2 protein (up to 50%) in IOSE-29EC, whereas no differe nce was observed in Bar protein levels. Therefore, down-regulated Bcl-2 by TGF beta may eventually induce apoptosis in IOSE-29EC cells. In contrast, n o difference was observed in Pax and Bcl-2 protein expression after treatme nt with activin. In conclusion, the present study indicates that activin an d TGF beta 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 TGF beta, whereas no difference was produce d in Bar protein by activin or TGF beta treatment or in Bcl-2 protein by ac tivin. These results suggest that activin and TGF beta may play a role in g rowth inhibition and induction of apoptosis in early neoplastic and tumorig enic stage of ovarian cancer.