Lipid metabolism is regarded as a hallmark of cancer. Sphingolipids, a family of structural and signaling lipids, have antiproliferative (ceramides) or pro-survival (sphingosine 1 phosphate [S1P]) function. The positive association between statin use and bladder cancer, unlike other cancers, suggests that lipid metabolism not affected by HMG-CoA reductase inhibition may contribute uniquely to this cancer. We conducted a hypothesis-generating study investigating associations between plasma sphingolipid metabolic enzymes and bladder cancer incidence and mortality in the Atherosclerosis Risk in Communities (ARIC) study. Among 10,129 men and women with proteomic profiling of plasma collected in 1993-1995, 158 incident bladder cancer cases and 47 bladder cancer deaths were ascertained over a median of 20 years of follow-up (164,013 person-years). Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for protein tertiles adjusted for age, race, sex, and known cancer risk factors including smoking status and pack-years smoked, and cholesterol-lowering medication use. Of the 6 sphingolipid enzymes, SPHK1 involved in S1P synthesis was associated with an increased risk of bladder cancer incidence (tertile [T]3 vs. 1: HR=1.74; 95% CI=1.15-2.63; p-trend=0.008) and bladder cancer mortality (T3 vs. 1: HR=2.39; 95% CI=1.02-5.61; p-trend=0.06). Associations for incidence were attenuated in lagged analyses suggesting potential reverse causation, while associations for mortality were unchanged. Our findings suggest sphingolipid metabolism, specifically enzymes involved in S1P synthesis, may contribute to bladder cancer etiology with stronger associations in subgroups with lower cholesterol. These findings motivate confirmatory investigation of plasma S1P in relation to bladder cancer outcomes.
Cancer prevention research (Philadelphia, Pa.). 2026 Jul 06 [Epub ahead of print]
Michael T Marrone, Evan Bagley, Kenneth R Butler, David J Couper, Corinne E Joshu, Elizabeth A Platz, Besim Ogretmen
Medical University of South Carolina Charleston, SC United States., University of Mississippi Medical Center Jackson, MS United States., University of North Carolina at Chapel Hill Chapel Hill, NC United States., Johns Hopkins Bloomberg School of Public Health Baltimore, MD United States., Johns Hopkins Bloomberg School of Public Health Baltimore United States.