Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells

Abstract

The RAS-RAF-MEK-extracellular signal-regulated kinase (ERK) pathway plays a pivotal role in various cellular responses, including cellular growth, differentiation, survival and motility. Constitutive activation of the ERK pathway has been linked to the development and progression of human cancers. Here, we reported that mitogen-activated protein kinase phosphatase (MKP)-3, a negative regulator of ERK1/2, lost its expression particularly in the protein level, was significantly correlated with high ERK1/2 activity in primary human ovarian cancer cells using quantitative reverse transcription-polymerase chain reaction and western blot analyses. Intriguingly, the loss of MKP3 protein was associated with ubiquitination/proteosome degradation mediated by high intracellular reactive oxygen species (ROS) accumulation such as hydrogen peroxide in ovarian cancer cells. Functionally, short hairpin RNA knock down of endogenous MKP3 resulted in increased ERK1/2 activity, cell proliferation rate, anchorage-independent growth ability and resistance to cisplatin in ovarian cancer cells. Conversely, enforced expression of MKP3 in MKP3-deficient ovarian cancer cells significantly reduced ERK1/2 activity and inhibited cell proliferation, anchorage-independent growth ability and tumor development in nude mice. Furthermore, the enforced expression of MKP3 succeeded to sensitize ovarian cancer cells to cisplatin-induced apoptosis in vitro and in vivo. These results suggest a molecular mechanism by which 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 tumorigenicity and chemoresistance of human ovarian cancer cells.

Hydrogen peroxide primes heart regeneration with a derepression mechanism

“…In contrast to previous reports on a negative role of p38 MAPK in mammalian and zebrafish heart regeneration [44,45], our data support that H 2 O 2 in the epicardium (Figure 1) is essential for elevating phosphorylation of Erk1/2 MAPK through repression of Dusp6 during zebrafish heart regeneration ( Figures 3-5 and 7). Our data are aligned well with the previous reports that H 2 O 2 directly oxidizes Dusp6 in TNFα-induced cell death and ovarian cancers, leading to ubiquitination and subsequent proteasome degradation of Dusp6 and thus aberrant Erk1/2 activation [37,38] (Figure 5). The elevated pErk1/2 in the epicardium might then activate soluble factors at transcriptional and/or post-transcrip-npg www.cell-research.com | Cell Research tional levels, which in turn bind to their receptors in the myocardium and promote myocardial proliferation and regeneration.…”

“…Previous reports have shown that H 2 O 2 directly oxidizes Dusp6 in TNFα-induced cell death and ovarian cancers, and that oxidized Dusp6 is prone to degradation, leading to aberrant Erk1/2 activation [37,38]. Dusp6-knockout mice show greater proliferation of myocytes [39], but the function of Dusp6 in cardiac regeneration is unknown.…”

Essential role of Fbxl14 ubiquitin ligase in regulation of vertebrate axis formation through modulating Mkp3 level

“…Mkp3, a novel target of Fbxl14 in this study, is involved in the development of cancer and has been suggested as a candidate tumor suppressor protein [9]. Moreover, Mkp3 has also been correlated with chemoresistance of cancer cells [10,11]. Taken together, these findings indicate that Fbxl14 has the potential to play a role in cancer development, and they may help to elucidate the mechanism of Mkp3-related chemoresistance.…”

Identification of Expression Signatures Predictive of Sensitivity to the Bcl-2 Family Member Inhibitor ABT-263 in Small Cell Lung Carcinoma and Leukemia/Lymphoma Cell Lines

“…For example, loss of DUSP6/MKP3, a phosphatase that dephosphorylates extracellular signal-regulated kinase 1/2 (and has tumor suppressive effects), has been shown to increase tumorgenicity and chemoresistance (44). DUSP6 expression is high in 10 of 19 sensitive lines, whereas its expression is at or below background levels in five of six resistant leukemia/lymphoma cell lines, as would be predicted if loss of expression leads to chemoresistance.…”