Adenocarcinoma, Apoptosis, Blotting, Western, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Cyclooxygenase 2, Enzyme Inhibitors, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lung Neoplasms, Male, Prognosis, Reverse Transcriptase Polymerase Chain Reaction, Thromboxane B2, Thromboxane-A Synthase, Tissue Array Analysis
BACKGROUND: Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease.
METHODS: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression.
RESULTS: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis.
CONCLUSION: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
Medical Pathology | Pathology
Cathcart MC, Gately K, Cummins R, Kay E, O'Byrne KJ, Pidgeon GP. Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer. Molecular Cancer. 2011;10:25.