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Logo of bmccancBioMed Centralsearchsubmit a manuscriptregisterthis articleBMC Cancer
 
BMC Cancer. 2010; 10: 95.
Published online 2010 March 12. doi:  10.1186/1471-2407-10-95
PMCID: PMC2850900
Copyright ©2010 Tai et al; licensee BioMed Central Ltd.
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
Cheng-Jeng Tai,1 Alexander TH Wu,2 Jeng-Feng Chiou,2 Hsun-Jin Jan,3 Hon-Jian Wei,4 Chung-Huei Hsu,5 Che-Tong Lin,6 Wen-Ta Chiu,7 Cheng-Wen Wu,8 Horng-Mo Lee,corresponding author3 and Win-Ping Dengcorresponding author9
1Cancer Center and Section of Haematology-Oncology, Department of Internal Medicine, Taipei Medical University and Hospital, Taipei, Taiwan
2Cancer Center and Department of Radiation Oncology, Taipei Medical University and Hospital, Taipei, Taiwan
3Graduate Institute of Cell and Molecular Biology, Taipei, Taiwan
4Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
5Department of Nuclear Medicine, Taipei Medical University, Taipei, Taiwan
6Graduate Institute of Oral Rehabilitation Sciences, Taipei Medical University, Taipei, Taiwan
7Wan-Fang Hospital and Taipei Medical University, Taipei, Taiwan
8Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
9Institute of Biomedical Materials and Engineering and Center of Excellence for Cancer Research (CECR), Taipei Medical University, Taipei, Taiwan
corresponding authorCorresponding author.
Cheng-Jeng Tai: cjtai/at/tmu.edu.tw; Alexander TH Wu: chaw1211/at/tmu.edu.tw; Jeng-Feng Chiou: sjfchiou/at/ms68.hinet.net; Hsun-Jin Jan: j66324/at/hotmail.com; Hon-Jian Wei: m212092003/at/tmu.edu.tw; Chung-Huei Hsu: chhsu/at/tmu.edu.tw; Che-Tong Lin: chetong/at/tmu.edu.tw; Wen-Ta Chiu: wtchiu/at/tmu.edu.tw; Cheng-Wen Wu: ken/at/nhiri.org.tw; Horng-Mo Lee: leehorng/at/tmu.edu.tw; Win-Ping Deng: wpdeng/at/ms41.hinet.net
Received July 27, 2009; Accepted March 12, 2010.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
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 PPARγ 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-γ (PPARγ) 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 PPARγ agonists could be explored for combined chemotherapy.
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