title: Thromboxane A2 exerts promoting effects on cell proliferation through mediating cyclooxygenase-2 signal in lung adenocarcinoma cells.
abstract: BACKGROUND
  Lung cancer concerns a worldwide health problem and the efficacy of available treatments is unsatisfactory. Recently, thromboxane A2 (TXA2) synthase (TXAS) and receptor (TXA2R) have been documented to play a role in lung cancer development. Therefore, dual TXA2R modulator (i.e., the dual blocker of TXAS and TXA2R) may be more efficacious to kill lung tumor cells than single TXAS inhibitor or TXA2R antagonism. The close relationship between cyclooxygenase (COX)-2 and TXAS also raises whether or how TXA2 contributes to the oncogenic activity of COX-2. This study is therefore conducted to answer these questions.
  
  
  METHODS
  Various inhibitors and siRNA were used to evaluate the roles of TXA2 and COX-2 in the proliferation and apoptosis of lung adenocarcinoma cells. Cell proliferation was detected using both MTS ELISA and BrdU labeling ELISA. Cell cycle distribution and apoptosis were examined by flow cytometric analysis. TXB2 level, reflecting the biosynthesis of TXA2, was detected by peroxidase-labeled TXB2 conjugates using an enzyme immunoassay kit. Western blotting was performed to evaluate many biomarkers for cell cycles, apoptosis and proliferation. The levels of COXs were screened by reverse transcriptase and real-time quantitative PCR.
  
  
  RESULTS
  We found either single TXAS inhibitor/TXA2R antagonist or the dual TXA2 modulators offered a similar inhibition on cell proliferation. Moreover, inhibition of TXA2 arrested cells at the G2/M phase and induced apoptosis. It is further demonstrated that TXA2 was able to function as a critical mediator for tumor-promoting effects of COX-2 in lung adenocarcinoma cells.
  
  
  CONCLUSIONS
  The present study has for the first shown that dual TXA2 modulators and the single blocker of TXAS or TXA2R offer a similar inhibitory role in lung adenocarcinoma cell proliferation and that the tumor-promoting effects of COX-2 can largely be relayed by TXA2. Thus, TXA2 should be regarded as a critical molecule in COX-2-mediated tumor growth and a valuable target against lung cancer.
authors.affiliation: Department of Rheumatology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510006, China, ry_huang@hotmail.com.
authors.forename: Run-Yue
authors.initials: RY
authors.lastname: Huang
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Li
authors.forename: Hui-Zhen
authors.initials: HZ
authors.lastname: Guo
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.forename: Ming-Yue
authors.initials: MY
authors.lastname: Li
authors.forename: George Gong
authors.initials: GG
authors.lastname: Chen
authors.forename: Xing
authors.initials: X
authors.lastname: Zeng
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005231:Fatty Acids, Unsaturated; D005434:Flow Cytometry; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009578:Nitrobenzenes / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D017482:Receptors, Thromboxane / Q000819:agonists / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; C434802:BM 567; D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D009578:Nitrobenzenes; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D013930:Thromboxane-A Synthase; C039936:furegrelate