PMID- 20226009
OWN - NLM
STAT- MEDLINE
DCOM- 20101228
LR  - 20181113
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 10
DP  - 2010 Mar 12
TI  - The investigation of mitogen-activated protein kinase phosphatase-1 as a 
      potential pharmacological target in non-small cell lung carcinomas, assisted by 
      non-invasive molecular imaging.
PG  - 95
LID - 10.1186/1471-2407-10-95 [doi]
AB  - BACKGROUND: Invasiveness and metastasis are the most common characteristics of 
      non small cell lung cancer (NSCLC) and causes of tumour-related morbidity and 
      mortality. Mitogen-activated protein kinases (MAPKs) signalling pathways have 
      been shown to play critical roles in tumorigenesis. However, the precise 
      pathological role(s) of mitogen-activated protein kinase phosphatase-1 (MKP-1) in 
      different cancers has been controversial such that the up-regulation of MKP-1 in 
      different cancers does not always correlate to a better prognosis. In this study, 
      we showed that the induction of MKP-1 lead to a significant retardation of 
      proliferation and metastasis in NSCLC cells. We also established that 
      rosiglitazone (a PPARgamma agonist) elevated MKP-1 expression level in NSCLC 
      cells and inhibited tumour metastasis. METHODS: Both wildtype and dominant 
      negative forms of MKP-1 were constitutively expressed in NSCLC cell line H441GL. 
      The migration and invasion abilities of these cells were examined in vitro. MKP-1 
      modulating agents such as rosiglitazone and triptolide were used to demonstrate 
      MKP-1's role in tumorigenesis. Bioluminescent imaging was utilized to study 
      tumorigenesis of MKP-1 over-expressing H441GL cells and anti-metastatic effect of 
      rosiglitazone. RESULTS: Over-expression of MKP-1 reduced NSCLC cell proliferation 
      rate as well as cell invasive and migratory abilities, evident by the reduced 
      expression levels of MMP-2 and CXCR4. Mice inoculated with MKP-1 over-expressing 
      H441 cells did not develop NSCLC while their control wildtype H441 inoculated 
      littermates developed NSCLC and bone metastasis. Pharmacologically, 
      rosiglitazone, a peroxisome proliferator activated receptor-gamma (PPARgamma) 
      agonist appeared to induce MKP-1 expression while reduce MMP-2 and CXCR4 
      expression. H441GL-inoculated mice receiving daily oral rosiglitazone treatment 
      demonstrated a significant inhibition of bone metastasis when compared to mice 
      receiving sham treatment. We found that rosiglitazone treatment impeded the 
      ability of cell migration and invasion in vitro. Cells pre-treated with 
      triptolide (a MKP-1 inhibitor), reversed rosiglitazone-mediated cell invasion and 
      migration. CONCLUSION: The induction of MKP-1 could significantly suppress the 
      proliferative and metastatic abilities of NSCLC both in vitro and in vivo. 
      Therefore, MKP-1 could be considered as a potential therapeutic target in NSCLC 
      therapy and PPARgamma agonists could be explored for combined chemotherapy.
FAU - Tai, Cheng-Jeng
AU  - Tai CJ
AD  - Graduate Institute of Cell and Molecular Biology, Taipei, Taiwan.
FAU - Wu, Alexander Th
AU  - Wu AT
FAU - Chiou, Jeng-Feng
AU  - Chiou JF
FAU - Jan, Hsun-Jin
AU  - Jan HJ
FAU - Wei, Hon-Jian
AU  - Wei HJ
FAU - Hsu, Chung-Huei
AU  - Hsu CH
FAU - Lin, Che-Tong
AU  - Lin CT
FAU - Chiu, Wen-Ta
AU  - Chiu WT
FAU - Wu, Cheng-Wen
AU  - Wu CW
FAU - Lee, Horng-Mo
AU  - Lee HM
FAU - Deng, Win-Ping
AU  - Deng WP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100312
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (CXCR4 protein, human)
RN  - 0 (Receptors, CXCR4)
RN  - EC 3.1.3.48 (Dual Specificity Phosphatase 1)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
SB  - IM
MH  - Animals
MH  - Carcinoma, Non-Small-Cell Lung/*enzymology
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Dual Specificity Phosphatase 1/*metabolism
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Luminescence
MH  - Lung Neoplasms/*enzymology
MH  - MAP Kinase Signaling System
MH  - Matrix Metalloproteinase 2/biosynthesis
MH  - Mice
MH  - Mice, SCID
MH  - Molecular Imaging/methods
MH  - Neoplasm Invasiveness
MH  - Neoplasm Metastasis
MH  - Receptors, CXCR4/biosynthesis
PMC - PMC2850900
EDAT- 2010/03/17 06:00
MHDA- 2010/12/29 06:00
PMCR- 2010/03/12
CRDT- 2010/03/16 06:00
PHST- 2009/07/27 00:00 [received]
PHST- 2010/03/12 00:00 [accepted]
PHST- 2010/03/16 06:00 [entrez]
PHST- 2010/03/17 06:00 [pubmed]
PHST- 2010/12/29 06:00 [medline]
PHST- 2010/03/12 00:00 [pmc-release]
AID - 1471-2407-10-95 [pii]
AID - 10.1186/1471-2407-10-95 [doi]
PST - epublish
SO  - BMC Cancer. 2010 Mar 12;10:95. doi: 10.1186/1471-2407-10-95.