The Role Of The TRAIL And Its Receptors In Apoptosis Of Ovarian Cancinoma Cells

Objective: To investigate the expression of TRAIL and its receptors in epithelial ovarian carcinoma and normal ovarian tissues. To study the effects of TRAIL with or without chemotherapeutic drugs in apoptosis of ovarian carcinoma cell line SKOV3 and the expression changes of DR4, DR5 in SKOV3 cells influenced by chemotherapeutic drugs. Furthermore, to clarify the tumor growth inhibition effects and toxic effects of TRAIL in ovarian tumor xenografts in nude mice.Methods: The expressions of TRAIL, DR4, and DcRl were studied in 21 cases of normal ovaries and 37 cases of epithelial ovarian carcinoma by means of immunohistochemistry. The effects of treatment with TRAIL alone and/or chemotherapeutic drugs on SKOV3 cells growth inhibition were measured by MTT assay and the changes of DR4 and DR5 mRNA were detected by RT-PCR technique. The cell cycle, and apoptosis index (AI) were analyzed by Flow Cytometry (FCM). We established peritoneal implantation nude mice models of SKOV3 ovarian carcinoma cell and injected TRAIL and/or DDP in peritoneal cavity. The weight of implantation tumor was tested by electronic scale and the function of liver and kidney was investigated byHITACT 7600 Automatic Analyzer . The expression of DR4 and DR5 of implantation tumor was studied by RT-PCR technique .All data were analyzed by SPSS 10.0 software package.Results: (1) The expressions of DR4 and DcRl in epithelial ovarian carcinoma were lower than those of normal ovary. (2) The positive expression ratio of DR4 in differentiated ovarian carcinoma was 92.31%, and 62.50% in undifferentiated ones. There was no relationship between the expression of TRAIL and its receptors and clinical stage, histologic type, lymph node metastasis. (3) There was no significant correlation between the expressions of TRAIL and those of DR4, DcRl. (4) Soluble TRAIL protein had the inhibiting effect to the growth SKOV3 cells. (5) DDP and Adriamycin increased the growth-inhibiting ability of TRAIL to SKOV3 cells. (6) The apoptotic indexes of SKOV3 cells detected by FCM were 5.9%, 13.4% and 39.5% in control group, TRAIL group and TRAIL plus DDP group, respectively. (7) DDP increased the expression of DR5 in SKOV3 cells by 1.95 fold than control group and by 1.54 times for the expression of DR4 than control one (p<0.05). (8) The weights of tumor in TRAIL intervening group, DDP group, and TRAIL plus DDP intervening group were significantly decreased than that in control one (p<0.05). (9) The determinations of serum BUN and Crea in DDP interfering nude mice were increased significantly, and the ALT was higher in mice dealed with TRAIL plus DDP. (10) DDP increased significantly the expression of DR5 in SKOV3 implantated tumor tissues in nude mice by 2.24 fold. Furthermore, DDP strengthened significantly the expression of DR4 in SKOV3 implantated tumor tissues by 1.82 fold (p<0.05).Conclusions: (1) The expressions of DR4 and DcRl in epithelial ovarian carcinoma are lower than those of normal ovary. (2) The expression of DR4 in epithelial ovarian carcinoma is decreased with the falling of the differentiation status of ovarian carcinoma. (3) There is no correlation of the expression between pro-apoptotic receptor DR4 and anta-apoptotic receptor DcRl. (4) Soluble TRAIL has the effect to inhibit the growth of SK0V3 cells. (5) The combination use of TRAIL and DDP increases significantly the inhibiting ratio to SKOV3 cells. (6) The AI of SK0V3 cells is raised after TRAIL intervened. (7) DDP can increase the expressions of DR4 and DR5 in SK0V3 cells. (8) TRAIL and DDP have the significant effect to inhibit the growth of implantated tumor in nude mice. (9) DDP may influence the renal function of nude mice. However, there is no significant change in hepatic function induced by TRAIL. (10) DDP may improve the expressions of DR5 and DR4 in SKOV3 implantated tumor in nude mice.