Publications (4)15.13 Total impact
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Article: Metformin Enhances Cisplatin Cytotoxicity by Suppressing Stat3 Activity Independently of the LKB1-AMPK Pathway.
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ABSTRACT: Metformin has been used as a first line treatment in patients with type 2 diabetes and is reported to reduce cancer risk and progress by activating the LKB1-AMPK pathway. Cisplatin remains the main drug for treating advanced non-small-cell lung cancer; however, drug resistance often develops through several mechanisms during the treatment course including one mediated by the activation of the IL-6/Stat3 pathway, related to ROS generation. This study demonstrated a correlation between Stat3 phosphorylation and cisplatin cytotoxicity using AS2 (PC14PE6/AS2)-derived cell lines (AS2/S3C) that contained constitutively active Stat3 plasmids as a model. A Stat3 inhibitor (JSI-124) enhanced the cisplatin sensitivity in AS2 cells, whereas metformin inhibited Stat3 phosphorylation and enhanced cisplatin cytotoxicity. By contrast, another AMPK activator (AICAR) failed to produce these effects. LKB1-AMPK silencing by siRNA or mTOR inhibition by rapamycin or pp242 did not alter the effect of metformin on Stat3 activity suppression, suggesting that metformin can modulate the Stat3 pathway through an LKB1-AMPK and probable MTOR-independent mechanism. Metformin also inhibited cisplatin-induced ROS production and autocrine IL-6 secretion in AS2 cells. Both mechanisms contribute to the ability of metformin to suppress Stat3 activation in cancer cells, which resulted in decreased VEGF secretion by cancer cells. The growth of subcutaneous tumor xenografts was significantly delayed by a combination of cisplatin and metformin. This is the first study to demonstrate that metformin suppresses Stat3 activation via LKB1-AMPK-MTOR independent but ROS and autocrine IL6 production-related pathways. Thus, metformin helps to overcome tumor drug resistance by targeting Stat3.American Journal of Respiratory Cell and Molecular Biology 03/2013; · 5.13 Impact Factor -
Article: Apolipoprotein E expression promotes lung adenocarcinoma proliferation and migration and as a potential survival marker in lung cancer.
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ABSTRACT: Many human lung cancer cell lines express apolipoprotein E (ApoE), especially cells derived from malignant pleural effusions (MPE) in patients with lung adenocarcinoma. This study aimed to investigate the influence of ApoE expression on lung cancer. In lung cancer tissues, ApoE expression was more frequently found in malignant pleural effusions (MPE)-associated lung adenocarcinoma than in lung adenocarcinoma or squamous cell carcinoma without MPE (P<0.05), indicating that ApoE is associated with the pathogenesis of MPE in patients with lung adenocarcinoma. Next, we examined the roles of ApoE in an MPE-derived lung adenocarcinoma cell line that endogenously over-expresses ApoE, PC14PE6/AS2 (AS2). In that experiment we inhibited ApoE expression by transfection of a plasmid carrying ApoE siRNAs into AS2 cells to generate AS-S2 and AS-S3 cells. Compared to vector-control cells and parental AS2 cells, AS2-S2 and AS2-S3 cells grew slower (P<0.05), were more sensitive to cisplatin, and had significantly impaired cellular migration (P<0.05). Furthermore, over-expression of ApoE was independently associated with poor survival in lung adenocarcinoma patients who had MPE at the time of diagnosis (P<0.001). Conclusively, ApoE over-expression promotes cancer proliferation and migration and contributes to an aggressive clinical course in patients with lung adenocarcinoma and MPE.Lung cancer (Amsterdam, Netherlands) 01/2011; 71(1):28-33. · 3.14 Impact Factor -
Article: Single cell phospho-specific flow cytometry can detect dynamic changes of phospho-Stat1 level in lung cancer cells.
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ABSTRACT: Single cell phospho-specific flow cytometry (SCPFC) enables the investigation of signaling network interactions and the categorization of disease outcome. While this method has been successfully used to study hematologic disorders, its application on solid tumors has not been examined. This study aimed to demonstrate the ability of SCPFC to detect dynamic changes of Tyrosine phospho-Stat1 (pStat1) in solid tumor models and in human tumor samples. In the human lung cancer cell line PC14PE6/AS2, the fluorescence intensity changes of pStat1 after IFN-γ stimulation were compatible to results obtained by Western blot analysis. In metastatic animal models, cancer cells from subcutaneous tumors, malignant ascites, and peritoneal tumors responded to IFN-γ. The pStat1 was activated in these cells after IFN-γ stimulation, with a 1.5- to 2.5-fold increase in fluorescence intensity compared to the unstimulated control. To examine the potential clinical application of SCPFC, cancer cells were collected from malignant pleural effusions (MPEs) of lung cancer patients to observe the activation of pStat1 after IFN-γ stimulation. Cell apoptosis after cisplatin treatment was evaluated by Annexin V staining, which showed that MPE cancer cells with higher pStat1 changes after IFN-γ stimulation were more resistant to cisplatin. In conclusion, there is a preliminary application of SCPFC to solid tumors and links to drug sensitivity are promising.Cytometry Part A 11/2010; 77(11):1008-19. · 3.73 Impact Factor -
Article: Angiogenetic biomarkers in non-small cell lung cancer with malignant pleural effusion: correlations with patient survival and pleural effusion control.
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ABSTRACT: To evaluate how the angiogenetic biomarkers vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and interleukin-8 (IL-8) in the fluid of non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE) correlate with patient survival and pleural effusion control. Prospective study. From April 1, 1998 to April 30, 2005, we used thoracoscopic biopsy to collect pleural specimens and pleural effusion from 97 patients with NSCLC and MPE. Paired blood samples were harvested. We used enzyme-linked immunosorbent assays to evaluate levels of angiogenic factors in MPE and blood, and immunohistochemical staining to evaluate them in pleural specimens. Related data, such as patient survival and PE control, were collected for correlation analysis. Smoking and PE VEGF >1350 ng/mL were both significant negative predictors of patient survival. A trapped lung was the only significant factor for poor PE control. The serum level, the amount of PE, and the number of red blood cells in PE correlated well with PE VEGF level. Immunohistochemical staining of pleural samples showed that VEGF was secreted by both mesothelial and tumor cells. The level of PE IL-8 weakly correlated with PE VEGF, and the level of bFGF was not significant. PE VEGF was a useful angiogenetic factor for the amount of fluid in patients with NSCLC and MPE. In addition to smoking, PE VEGF >1350 ng/mL was a significant negative predictor of patient survival.Lung cancer (Amsterdam, Netherlands) 01/2009; 65(3):371-6. · 3.14 Impact Factor
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Institutions
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2013
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National Cheng Kung University Hospital
Tainan, Taiwan, Taiwan
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2010–2011
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National Cheng Kung University
- College of Medicine
Tainan, Taiwan, Taiwan
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