Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer.

Abstract

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.

• Authors: Mary-Clare Cathcart, Kathy Gately, Robert Cummins, Elaine Kay, Kenneth J O'Byrne, Graham P Pidgeon
• Journal: Molecular cancer (Mol Cancer) Vol. 10 Pg. 25 (Mar 09 2011) ISSN: 1476-4598 [Electronic] England
• PMID: 21388528 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Thromboxane B2
• Cyclooxygenase 2
• Thromboxane-A Synthase

Topics

• Adenocarcinoma (drug therapy, enzymology, pathology)
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (metabolism)
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Lung Neoplasms (drug therapy, enzymology, pathology)
• Male
• Prognosis
• Reverse Transcriptase Polymerase Chain Reaction
• Thromboxane B2 (metabolism)
• Thromboxane-A Synthase (antagonists & inhibitors, genetics, metabolism)
• Tissue Array Analysis