Urinary Thromboxane B2 and Lethal Prostate Cancer in African American Men

Abstract

Background 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. Methods 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. Median survival follow-up was 8.4 years with 246 deaths among cases. Aspirin use was assessed with a questionnaire. Race/ethnicity was self-reported. Results 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]= 1.13–2.00) but not EA men (OR = 1.07, 95% CI = 0.82–1.40), suggesting upregulated TXA2 synthesis in AA men with prostate cancer. High TXB2 was positively associated with metastatic prostate cancer (OR = 2.60, 95%CI = 1.08–6.28), compared with low (≤ median) TXB2. Furthermore, high TXB2 was also associated with all-cause (adjusted hazard ratio = 1.59, 95% CI = 1.06–2.40) and prostate cancer-specific mortality (hazard ratio = 4.74, 95%CI = 1.62–13.88 in AA men only. Conclusion We report a distinct association of TXB2 with prostate cancer outcomes in AA men. In this high-risk group of men, upregulation of TXA2/TXB2 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.

Urinary PGE-M in Men with Prostate Cancer

“…However, Drew et al reported approximately 20-25% of participants in the ASPIRED study who were randomized to 81 or 325 mg/day of aspirin experienced no inhibition or even an increase in PGE-M from baseline despite demonstrating a strong inhibition of urinary thromboxane B2 [22]. This finding is consistent with our data, where in a previous study, using the same cohort of participants, we reported strong thromboxane B2 inhibition in aspirin users across both cases and controls [38]. This suggests that the participants in our study are not nonresponders to aspirin, but rather, aspirin use mechanistically is not targeting PGE-M in these men.…”

Integrated analysis of plasma and urine reveals unique metabolomic profiles in idiopathic inflammatory myopathies subtypes

“…TXB2 is a stable metabolite of thromboxane A2 (TXA2), which is derived from cyclooxygenase (COX) and PLTs. TXA2 has been linked to cardiovascular diseases, Type 1 and 2 diabetes, chronic inflammatory diseases, and tumour metastasis 22,23 . Consistent with our study, increased expression of enzymes in the COX pathway was discovered in muscles from DM/PM patients 24 .…”

“…TXA2 has been linked to cardiovascular diseases, Type 1 and 2 diabetes, chronic inflammatory diseases, and tumour metastasis. 22,23 Consistent with our study, increased expression of enzymes in the COX pathway was discovered in muscles from DM/PM patients. 24 These prostanoid signalling molecules play an important role in muscle inflammation and atrophy.…”

Profiles of circulating fatty acids are population-specific and linked to prostate cancer

“…Noteworthy, arachidonic acid can be further metabolized by the cyclooxygenase and 5-lipoxygenase enzymes, resulting in the synthesis of pro-in ammatory eicosanoids. One eicosanoid, the pro-metastatic thromboxane A2, has recently been linked by our group to an increased risk of lethal prostate cancer among African American men 34 . Nonetheless, the FADS1/2 locus has not been previously linked to prostate cancer in most studies 32 .…”