Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer

Jody Vykoukal; Johannes F. Fahrmann; Justin R. Gregg; Zhe Tang; Spyridon Basourakos; Ehsan Irajizad; Sanghee Park; Guang Yang; Chad J. Creighton; Alia Fleury; Jeffrey Mayo; Adriana Paulucci-Holthauzen; Jennifer B. Dennison; Eunice Murage; Christine B. Peterson; John W. Davis; Jeri Kim; Samir Hanash; Timothy C. Thompson

doi:10.1038/s41467-020-17645-z

Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer

Jody Vykoukal, Johannes F. Fahrmann, Justin R. Gregg, Zhe Tang, Spyridon Basourakos, Ehsan Irajizad, Sanghee Park, Guang Yang, Chad J. Creighton, Alia Fleury, Jeffrey Mayo, Adriana Paulucci-Holthauzen, Jennifer B. Dennison, Eunice Murage, Christine B. Peterson, John W. Davis, Jeri Kim, Samir Hanash, Timothy C. Thompson

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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.

Original language	English (US)
Article number	4279
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17645-z
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Vykoukal, J., Fahrmann, J. F., Gregg, J. R., Tang, Z., Basourakos, S., Irajizad, E., Park, S., Yang, G., Creighton, C. J., Fleury, A., Mayo, J., Paulucci-Holthauzen, A., Dennison, J. B., Murage, E., Peterson, C. B., Davis, J. W., Kim, J., Hanash, S., & Thompson, T. C. (2020). Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer. Nature communications, 11(1), Article 4279. https://doi.org/10.1038/s41467-020-17645-z

Vykoukal, J , Fahrmann, JF , Gregg, JR, Tang, Z, Basourakos, S, Irajizad, E, Park, S, Yang, G, Creighton, CJ, Fleury, A, Mayo, J, Paulucci-Holthauzen, A, Dennison, JB, Murage, E, Peterson, CB , Davis, JW, Kim, J, Hanash, S & Thompson, TC 2020, 'Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer', Nature communications, vol. 11, no. 1, 4279. https://doi.org/10.1038/s41467-020-17645-z

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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.",

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AU - Park, Sanghee

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AU - Creighton, Chad J.

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AU - Mayo, Jeffrey

AU - Paulucci-Holthauzen, Adriana

AU - Dennison, Jennifer B.

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AU - Peterson, Christine B.

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AU - Kim, Jeri

AU - Hanash, Samir

AU - Thompson, Timothy C.

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N2 - 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.

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Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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