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.
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.


CONCLUSIONS
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.
Graduate Institute of Cell and Molecular Biology, Taipei, Taiwan.
Cheng-Jeng
CJ
Tai
Alexander Th
AT
Wu
Jeng-Feng
JF
Chiou
Hsun-Jin
HJ
Jan
Hon-Jian
HJ
Wei
Chung-Huei
CH
Hsu
Che-Tong
CT
Lin
Wen-Ta
WT
Chiu
Cheng-Wen
CW
Wu
Horng-Mo
HM
Lee
Win-Ping
WP
Deng
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D049449:Luminescence; D008175:Lung Neoplasms / Q000201:enzymology*; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D016513:Mice, SCID; D057054:Molecular Imaging / Q000379:methods; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019718:Receptors, CXCR4 / Q000096:biosynthesis
C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; D054638:Dual Specificity Phosphatase 1; D020778:Matrix Metalloproteinase 2