Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer
Abstract
Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressors that, together with plasma Cav-1, yield a prognostic signature for disease progression. Mechanistic studies of the underlying tumor supportive onco-metabolism reveal coordinated activities through which Cav-1 enables rewiring of cancer cell lipid metabolism towards a program of 1) exogenous sphingolipid scavenging independent of cholesterol, 2) increased cancer cell catabolism of sphingomyelins to ceramide derivatives and 3) altered ceramide metabolism that results in increased glycosphingolipid synthesis and efflux of Cav-1-sphingolipid particles containing mitochondrial proteins and lipids. We also demonstrate, using a prostate cancer syngeneic RM-9 mouse model and established cell lines, that this Cav-1-sphingolipid program evidences a metabolic vulnerability that is targetable to induce lethal mitophagy as an anti-tumor therapy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 27, 2020
- Source ID
- 10.1038/s41467-020-17645-z
Entities
People
- Adriana Paulucci-holthauzen
- Alia Fleury
- Chad J Creighton
- Christine B Peterson
- Ehsan Irajizad
- Eunice Murage
- Guang Yang
- Jeffrey Mayo
- Jennifer B. Dennison
- Jeri Kim
- Jody Vykoukal
- Johannes F. Fahrmann
- John W. Davis
- Justin R Gregg
- Samir M Hanash
- Sanghee Park
- Spyridon Basourakos
- Timothy C Thompson
- Zhe Tang
Organizations
- National Cancer Institute
- United States Department of Defense
- United States Department of Health and Human Services