An inhibitory effect on cell proliferation by blockage of the MAPK/estrogen receptor/MDM2 signal pathway in gynecologic cancer

Abstract Objective. We previously demonstrated that that the Ras/ER/ MDM2pathway was critical for NIH3T3 cell transformation. In this study, we examined the effect of blocking this pathway on cell growthin gynecologic cancer cells. Methods. (1) The levels of MDM2, ER, p53 and p21 in endometrial or ovarian cancer celllines were investigated and compared with that in normal cells by Western blots. (2) The effects of MEK-inhibitorand/or anti-estrogen, and siRNA of MDM2on cell growth, tumorigenicity in nude mice were examined. Results. The MDM2level was enhanced in cancer cellscompared with normal cells. Treatment with MEK inhibitor(U0126) resulted in a reduced MDM2level, enhanced p53 and p21 levels and inhibited cell growthby the induction of premature senescence. The effect of MEK inhibitoron cell growthwas affected by ER levels and functions. Treatment with low-dose MEK inhibitorin combination with anti-estrogen (ICI182,780) had a more inhibitory effect on cell growthcompared to treatment with MEK inhibitoror anti-estrogen alone in cancer cells. Down-regulation of the MDM2level by siRNA resulted in the inhibition of growth in cancer cells. Conclusion. The blockage of the MAPK/ER/ MDM2pathway suppress cell proliferation and it is supposed as a new molecular target therapy in estrogen-dependent gynecologic cancers, such as endometrial or ovarian cancer.