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.

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 overexpressing H441GL cells and anti−metastatic effect of rosiglitazone.

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.

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.

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