In vivo study of the effect of MDM2-p53 feedback loop on the sensitivity to cisplatin in ovarian cancer / 肿瘤研究与临床

ABSTRACT

Objective To investigate the effect of MDM2-p53 feedback loop on the sensitivity to cis- platin in ovarian cancer xenograft in vivo and explore its mechanism.Methods Human ovarian cancer cell line A2780 with wild type p53 was inoculated subcutaneously into the back of nude mice.When tumor nod- ules could be observed after 7 days of inoculation,the mice were randomly divided into 5 groups with each of 6 mice.Treatment group received an intratumoral injection of a combination of pCMV-MDM2-Lipofectamine and cisplatin.Control groupⅠwas injected with cisplatin,control groupⅡwas injected with pCMV-MDM2- Lipofectamine,control groupⅢwas injected with empty pCMV-Lipofectamine,control groupⅣwas injected with RPMI1640.General conditions and tumor growth rate were observed.The volume and the weight of the tumor were compared among these five groups.The expression of MDM2 and p53 in these tumors were de- tected by immunohistochemistry and Western blot.The changes of cell cycles in these tumors were examined by using flow cytometry assay.Results Tumor volume in treatment group[(0.321?0.086) cm~3]was significant- ly smaller than control groupⅠandⅡ[(1.832?0.165) cm~3 and (3.251?0.179) cm~3,respectively)].The weight of the treatment group [(0.513?0.089) g]was also significantly lower than control groupⅠandⅡ[(1.412?0.134) g,and (2.665?0.153) g,respectively)].There was a significant difference between control groupⅠandⅡ, but no difference between the other three control groups.Obvious MDM2 protein expression and pronounced S-phase arrest were observed in treatment group.However,control groupⅠwas with intact wild type p53,and arrested primarily in G_2/M phase.Conclusion MDM2 overexpression can increase cisplatin cytotoxicity on experimental ovarian cancer through inhibition of p53 expression and the loss of G_1 check point of cell cycle.