thromboxane-a2 and Prostatic-Neoplasms

Twenty patients with prostatic carcinoma were randomized to therapy with either oestrogens (n = 10) or orchidectomy (n = 10). Activators and inhibitors of coagulation were studied before treatment, 1.5 months and 6 months after the start of treatment. We found that the patients in the oestrogen group had already increased their factor VII level after 1.5 months (P less than 0.001) and this increased level persisted after 6 months. Factor X tended to increase after 1.5 months and this increase reached significance after 6 months (P less than 0.01). In the orchidectomy groups there was a significant increase in factor X at 6 months (P less than 0.01) and, in addition, antithrombin III (AT III) was increased at this time. Furthermore, there was a parallelism between the increase in factor VII and electrocardiographic evidence of increased coronary insufficiency (r = 0.60; P less than 0.025; n = 15). We found a significant increase of thromboxane as evidenced by the major urinary metabolite 2,3-dinorthromboxane B2 in the oestrogen group as compared to the orchidectomy group. In summary, patients with prostatic cancer during long-term oestrogen treatment were found to have increased levels of factor VII, factor VIII:C and fibrinogen. In addition these patients showed increased formation of thromboxane. The changes imply a hypercoaguable state and platelet activation. No such signs were found after orchidectomy. The findings in the oestrogen group might explain the continuously increased risk of cardiovascular complications during long-term oestrogen therapy.

Topics: Aged; Antigens; Blood Coagulation Disorders; Data Interpretation, Statistical; Epoprostenol; Estradiol; Ethinyl Estradiol; Exercise Test; Factor VII; Fibrinogen; Fibrinolysis; Humans; Male; Orchiectomy; Prospective Studies; Prostatic Neoplasms; Random Allocation; Thromboxane A2; Time Factors

Thromboxane A2 (TXA2) is a platelet- and cyclooxygenase-derived eicosanoid that has been linked to metastasis. We investigated the role of TXA2 in the development of lethal prostate cancer in African American (AA) and European American (EA) men.. We measured urinary 11-dehydrothromboxane B2 (TXB2), a stable metabolite of TXA2, with mass spectrometry. Samples were obtained from 977 cases and 1022 controls at time of recruitment. We applied multivariable logistic and Cox regression modeling to examine associations of TXB2 with prostate cancer and patient survival. The median survival follow-up was 8.4 years, with 246 deaths among cases. Aspirin use was assessed with a questionnaire. Race was self-reported.. Urinary TXB2 was inversely associated with aspirin use. High (>median) TXB2 was associated with prostate cancer in AA (adjusted odds ratio [OR] = 1.50, 95% confidence interval [CI] = 1.13 to 2.00) but not EA men (OR = 1.07, 95% CI = 0.82 to 1.40), suggesting upregulated TXA2 synthesis in AA men with prostate cancer. High TXB2 was positively associated with metastatic prostate cancer (OR = 2.60, 95% CI = 1.08 to 6.28) compared with low (≤median) TXB2. Furthermore, high TXB2 was also associated with all-cause (adjusted hazard ratio = 1.59, 95% CI = 1.06 to 2.40) and prostate cancer-specific mortality (hazard ratio = 4.74, 95% CI = 1.62 to 13.88) in AA men only.. We report a distinct association of TXB2 with prostate cancer outcomes in AA men. In this high-risk group of men, upregulation of TXA2 synthesis may promote metastasis and lethal disease. Our observation identifies a potential benefit of aspirin in preventing lethal prostate cancer through inhibition of TXA2 synthesis.

Topics: Aspirin; Black or African American; Humans; Male; Prostatic Neoplasms; Thromboxane A2; Thromboxane B2

Topics: Cell Line, Tumor; CpG Islands; DNA Methylation; Down-Regulation; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Male; Promoter Regions, Genetic; Prostatic Neoplasms; Protamines; Protein Isoforms; Receptors, Thromboxane A2, Prostaglandin H2; Repressor Proteins; Thromboxane A2; Transcription Factors; Up-Regulation

The prostanoid thromboxane (TX) A2 is increasingly implicated in neoplastic progression, including prostate cancer (PCa). Mechanistically, we recently identified protein kinase C-related kinase (PRK) 1 as a functional interactant of both the TPα and TPβ isoforms of the human T prostanoid receptor (TP). The interaction with PRK1 was not only essential for TPα/TPβ-induced PCa cell migration but also enabled the TXA2-TP axis to induce phosphorylation of histone H3 at Thr11 (H3Thr11), an epigenetic marker both essential for and previously exclusively associated with androgen-induced chromatin remodelling and transcriptional activation. PRK1 is a member of a subfamily of three structurally related kinases comprising PRK1/PKNα, PRK2/PKNγ and PRK3/PKNβ that are widely yet differentially implicated in various cancers. Hence, focusing on the setting of prostate cancer, this study investigated whether TPα and/or TPβ might also complex with PRK2 and PRK3 to regulate their activity and neoplastic responses. While TPα and TPβ were found in immune complexes with PRK1, PRK2 and PRK3 to regulate their activation and signalling, they do so differentially and in a TP agonist-regulated manner dependent on the T-loop activation status of the PRKs but independent of their kinase activity. Furthermore, TXA2-mediated neoplastic responses in prostate adenocarcinoma PC-3 cells, including histone H3Thr11 phosphorylation, was found to occur through a PRK1- and PRK2-, but not PRK3-, dependent mechanism. Collectively, these data suggest that TXA2 acts as both a neoplastic and epigenetic regulator and provides a mechanistic explanation, at least in part, for the prophylactic benefits of Aspirin in reducing the risk of certain cancers.

Topics: Adenocarcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Enzyme Activation; Epigenesis, Genetic; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HEK293 Cells; Histones; Humans; Male; Phosphorylation; Prostatic Neoplasms; Protein Binding; Protein Kinase C; Protein Kinase Inhibitors; Receptors, Thromboxane A2, Prostaglandin H2; Signal Transduction; Threonine; Thromboxane A2; Time Factors; Transfection

We investigated the potential involvement of the thromboxane A(2) (TXA(2)) pathway in human prostate cancer (PCa).. Expression of cyclooxygenase-2 (COX-2), TXA(2) synthase (TXS), and TXA(2) receptors (TPRs), the main actors of the TXA(2) pathway, was analyzed on serial tissue sections from 46 human PCa specimens.. The expression levels of COX-2, TXS, and TPRs were significantly higher in malignant than in corresponding nontumoral prostatic epithelial cells. Increased immunoreactivity for these antigens was also observed in high-grade prostate intraepithelial neoplasia (HGPIN) glands. COX-2, TXS, and TPR proteins usually displayed a coordinated overexpression pattern in PCa lesions, as assessed in serial tissue sections. Increased levels of these proteins in the tumors were all significantly associated with higher Gleason scores and pathologic stages.. Proteins specifically involved in the TXA(2) pathway are up-regulated in human PCa and their level of expression is associated with tumor extraprostatic extension and loss of differentiation. Our study is the first to examine simultaneously all key proteins involved in this pathway including TXA(2) receptors and results suggest that the TXA(2) pathway may be a potential target for PCa prevention/therapy.

Topics: Aged; Cell Differentiation; Cyclooxygenase 2; Gene Expression; Humans; Male; Membrane Proteins; Middle Aged; Neoplasm Staging; Prostatic Neoplasms; Protein Transport; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase