Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer.
Aged
Animals
Caveolin 1
/ blood
Cell Line, Tumor
Ceramides
/ metabolism
Disease-Free Survival
Gene Expression Regulation, Neoplastic
Glycosphingolipids
/ biosynthesis
Humans
Lipids
/ blood
Male
Mice, Inbred C57BL
Middle Aged
Prospective Studies
Prostatic Neoplasms
/ drug therapy
Pyrrolidines
/ pharmacology
Sphingolipids
/ metabolism
Sphingomyelins
/ metabolism
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 08 2020
27 08 2020
Historique:
received:
09
07
2019
accepted:
09
07
2020
entrez:
29
8
2020
pubmed:
29
8
2020
medline:
25
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32855410
doi: 10.1038/s41467-020-17645-z
pii: 10.1038/s41467-020-17645-z
pmc: PMC7453025
doi:
Substances chimiques
CAV1 protein, human
0
Caveolin 1
0
Ceramides
0
Glycosphingolipids
0
Lipids
0
Pyrrolidines
0
Sphingolipids
0
Sphingomyelins
0
eliglustat
DR40J4WA67
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4279Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA140388
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA223527
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NIH HHS
ID : S10 OD024976
Pays : United States
Organisme : NIDDK NIH HHS
ID : U2C DK119886
Pays : United States
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