MEK inhibition suppresses cell invasion and migration in ovarian cancers with activation of ERK1/2

Abstract

The extracellular-regulated kinase (ERK) signaling pathway plays an important role in regulating the malignant potential of a cancer cell. However, the effect of ERK signaling on cancer metastasis is not clearly understood. In the present study, we examined the status of ERK activation in 88 ovarian carcinomas in order to clarify the clinicopathological and prognostic significance of phosphorylated ERK1/2 (p-ERK1/2). p-ERK1/2 expression was identified in 37 (42%) of 88 ovarian carcinomas. There was no significant correlation between p-ERK1/2 expression and any of the clinicopathological factors tested. No significant correlation between p-ERK1/2 expression and overall survival was found in patients with ovarian carcinoma treated with platinum and taxane chemotherapy (P=0.426). Next, to clarify the role of ERK1/2 activation in ovarian cancers, we inactivated ERK1/2 in ovarian cancer cells using the MEK inhibitor, CI-1040, which prevents ERK1/2 activation. Based on simulated wound healing and invasion chamber assays, we found that the motility and invasion of ES2 and MPSC1 cells with p-ERK1/2 were significantly reduced (P<0.01) after treatment with CI-1040. By contrast, CI-1040 did not have any effect on KF28 cells, which were negative for p-ERK1/2. Twist was down-regulated simultaneously with p-ERK1/2 following treatment of ES2 and MPSC1 cells with CI-1040. Immunohistochemistry of ovarian carcinoma tissue revealed that the increased expression of p-ERK1/2 significantly correlated with Twist expression (P<0.01). The findings in this study provide new insight into the biological role of ERK signaling in ovarian carcinomas. Additionally, our observations have an important therapeutic implication for patients with ovarian cancers that express p-ERK1/2 as these patients may potentially benefit from CI-1040 therapy.