ERK-dependent MKP-1-mediated cisplatin resistance in human ovarian cancer cells.
Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is the MAPK phosphatase family member that negatively regulates MAPK signaling. Our previous study showed that MKP-1 is involved in cisplatin resistance, but the mechanism underlying its resistance is not understood. Here, we show that ERK2-mediated MKP-1 expression is critical for cisplatin resistance. Specifically, we showed that in the human ovarian cancer cell lines, cisplatin induces MKP-1 through phosphorylation. We also showed that inhibition of ERK2 activity by the MEK1/2 inhibitor U0126 or by small interfering RNA silencing decreases MKP-1 induction, leading to an increase in cisplatin-induced cell death, which mimicked the results obtained with cells in which MKP-1 is down-regulated. Importantly, down-regulation of ERK2 decreased cisplatin-induced MKP-1 phosphorylation, suggesting that MKP-1 phosphorylation depends on ERK2 activity. Furthermore, down-regulation of ERK2 or MKP-1 enhanced cisplatin-induced apoptosis. In addition, we showed that down-regulation of ERK2 or MKP-1 decreases the basal level of Bcl-2 protein and that inhibition of Bcl-2 activity sensitizes ovarian cancer cells to cisplatin. Collectively, our results indicate that induction of MKP-1 by cisplatin is through phosphorylation involving ERK signaling and that MKP-1 plays a critical role in ERK-mediated cisplatin resistance. Thus, our results suggest that targeting ERK-MKP-1 signaling could overcome cisplatin resistance in human ovarian cancer.
Wang
Juan
J
Program in Molecular Biology and Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Zhou
Jun-Ying
JY
Wu
Gen Sheng
GS
D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D034741:RNA, Small Interfering / Q000235:genetics
D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D002945:Cisplatin