Loss of MKP3 is associated with cisplatin-resistance and tumorigenicity of ovarian cancer

Abstract

The Ras-Raf-MEK-ERK1/2 (ERK) pathway plays a pivotal role in various cellular responses, including cellular growth, differentiation, survival and motility. Constitutive activation of ERK pathway due to increased exposure to growth factors, overexpression or mutation of receptor tyrosine kinases, Ras and Raf has been linked to many cancers. On the other hand, recent studies have found that the ERK activity is also modulated by a number of negative regulators. In this study, we identified Dual specificity MAPK phophatase 3 (MKP3), one of the negative regulators, was frequently downregulated and correlated with high ERK1/2 activity in human ovarian cancer. Intriguingly, we found that the loss of MKP3 was associated with high intracellular reactive oxygen species (ROS) accumulation such as H2O2. Mild treatment of ovarian cancer cells by hydrogen peroxide H2O2 resulted in MKP3 degradation through proteasome/ubiquitination pathway. Furthermore, enforced expression of MKP3 in MKP3-deficient ovarian cancer cells significantly reduced ERK1/2 activity, sensitized ovarian cancer cells to cisplatin-induced apoptosis, and inhibited cell proliferation and anchorage-independent growth ability in soft agar. These results suggest a molecular mechanism that the accumulation of ROS during ovarian cancer progression may cause the degradation of MKP3, which in turn leads to aberrant ERK1/2 activation and contributes to cisplatin-resistance and tumorigenicity of human ovarian cancer.