Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance.
Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 is a member of the MKP family that negatively regulates MAPK signaling. MKP-1 has been implicated in cell survival in response to stressful stimuli, including anticancer treatment, but its role in cisplatin resistance is not fully understood. Here, we show that cisplatin induces MKP-1 in several human cancer cell lines. Induction of MKP-1 by cisplatin was through the transcriptional mechanism regulated by extracellular signal-regulated kinase (ERK). Overexpression of MKP-1 rendered human lung cancer cells resistant to cisplatin. Conversely, down-regulation of MKP-1 by small interfering RNA silencing sensitized human lung cancer cells to cisplatin-induced cell death. Using primary mouse embryonic fibroblasts (MEF) from MKP-1 knockout mice, we show that induction of MKP-1 by cisplatin correlates with inactivation of c-Jun NH(2)-terminal kinase (JNK) but not ERK and p38. Furthermore, apoptosis induced by cisplatin was significant in MKP-1(-/-) MEFs, whereas such change was minimal in MKP-1(+/+) MEFs. More importantly, cisplatin-induced cell death is inhibited by blocking JNK but not ERK and p38 activities. Collectively, our results establish a critical role of JNK in cisplatin-induced apoptosis and suggest that MKP-1 is required for cisplatin resistance.
Wang
Zhaoqing
Z
Program in Molecular Biology and Human Genetics, Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Xu
Jing
J
Zhou
Jun-Ying
JY
Liu
Yusen
Y
Wu
Gen Sheng
GS
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D003609:Dactinomycin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D008175:Lung Neoplasms; D051379:Mice; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D034741:RNA, Small Interfering / Q000235:genetics
D000970:Antineoplastic Agents; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D003609:Dactinomycin; D054638:Dual Specificity Phosphatase 1; D053148:Caspase 3; D002945:Cisplatin