title: Constitutive Expression of MAP Kinase Phosphatase-1 Confers Multi-drug Resistance in Human Glioblastoma Cells.
abstract: OBJECTIVE
  Current treatment of glioblastoma after surgery consists of a combination of fractionated radiotherapy and temozolomide. However, it is difficult to completely remove glioblastoma because it has uncertain boundaries with surrounding tissues. Moreover, combination therapy is not always successful because glioblastoma has diverse resistances. To overcome these limitations, we examined the combined effects of chemotherapy and knockdown of mitogen-activated protein kinase phosphatase-1 (MKP-1).
  
  
  METHODS
  We used ten different anti-cancer drugs (cisplatin, cyclophosphoamide, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, mitomycin C, and vincristine) to treat glioblastoma multiforme (GBM) cells. Knockdown of MKP-1 was performed using siRNA and lipofectamine. The basal level of MKP-1 in GBM was analyzed based on cDNA microarray data obtained from the Gene Expression Omnibus (GEO) databases.
  
  
  RESULTS
  Anti-cancer drug-induced cell death was significantly enhanced by knockdown of MKP-1, and this effect was most prominent in cells treated with irinotecan and etoposide. Treatment with these two drugs led to significantly increased phosphorylation of c-Jun N-terminal kinase (JNK) in a time-dependent manner, while pharmacological inhibition of JNK partially inhibited drug-induced cell death. Knockdown of MKP-1 also enhanced drug-induced phosphorylation of JNK.
  
  
  CONCLUSIONS
  Increased MKP-1 expression levels could be the cause of the high resistance to conventional chemotherapeutics in human GBM. Therefore, MKP-1 is an attractive target for overcoming drug resistance in this highly refractory malignancy.
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon, Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Yu
authors.forename: Junseong
authors.initials: J
authors.lastname: Park
authors.forename: Jungsul
authors.initials: J
authors.lastname: Lee
authors.forename: Kyungsun
authors.initials: K
authors.lastname: Choi
authors.forename: Chulhee
authors.initials: C
authors.lastname: Choi
keywords: Anti-cencer drug resistance; Apoptosis; Chemotherpy; Dual specificity phosphatase 1; Glioblastoma; JNK mitogen-activated protein kinases