The roles of sphingosine kinases 1 and 2 in regulating the Warburg effect in prostate cancer cells

David G Watson, Francesca Tonelli, Manal Al Osaimi, Leon Williamson, Edmond Chan, Irina Gorshkova, Evgeny Berdyshev, Robert Bittman, Nigel J Pyne, Susan Pyne

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Two isoforms of sphingosine kinase, SK1 and SK2, catalyze the formation of the bioactive lipid sphingosine 1-phosphate (S1P) in mammalian cells. We have previously shown that treatment of androgen-sensitive LNCaP prostate cancer cells with a non-selective SK isoform inhibitor, 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi), induces the proteasomal degradation of SK1. This is concomitant with a significant increase in C22:0-ceramide and sphingosine levels and a reduction in S1P levels, resulting in the apoptosis of LNCaP cells. In contrast, we show here that a SK2-selective inhibitor, (R)-FTY720 methyl ether (ROME), increases sphingosine and decreases S1P levels but has no effect on ceramide levels and does not induce apoptosis in LNCaP cells. We also show that several glycolytic metabolites and (R)-S-lactoylglutathione are increased upon treatment of LNCaP cells with SKi, which induces the proteasomal degradation of c-Myc. These changes reflect an indirect antagonism of the Warburg effect. LNCaP cells also respond to SKi by diverting glucose 6-phosphate into the pentose phosphate pathway to provide NADPH, which serves as an antioxidant to counter an oxidative stress response. SKi also promotes the formation of a novel pro-apoptotic molecule called diadenosine 5',5'''-P(1),P(3)-triphosphate (Ap3A), which binds to the tumor suppressor fragile histidine triad protein (FHIT). In contrast, the SK2-selective inhibitor, ROME, induces a reduction in some glycolytic metabolites and does not affect oxidative stress. We conclude that SK1 functions to increase the stability of c-Myc and suppresses Ap3A formation, which might maintain the Warburg effect and cell survival, while SK2 exhibits a non-overlapping function.
LanguageEnglish
Pages1011-1017
Number of pages7
JournalCellular Signalling
Volume25
Issue number4
Early online date11 Jan 2013
DOIs
Publication statusPublished - Apr 2013

Fingerprint

Prostatic Neoplasms
Sphingosine
Protein Isoforms
Oxidative Stress
Apoptosis
Methyl Ethers
Pentose Phosphate Pathway
Glucose-6-Phosphate
Ceramides
NADP
Androgens
sphingosine kinase
Cell Survival
Antioxidants
Lipids
sphingosine 1-phosphate
Neoplasms
diadenosine triphosphate

Keywords

  • sphingosine kinase
  • glycolysis
  • Warburg effect
  • oxidative stress
  • diadenosine triphosphate
  • cancer
  • proteasome
  • LNCaP metabolome

Cite this

Watson, David G ; Tonelli, Francesca ; Al Osaimi, Manal ; Williamson, Leon ; Chan, Edmond ; Gorshkova, Irina ; Berdyshev, Evgeny ; Bittman, Robert ; Pyne, Nigel J ; Pyne, Susan. / The roles of sphingosine kinases 1 and 2 in regulating the Warburg effect in prostate cancer cells. In: Cellular Signalling. 2013 ; Vol. 25, No. 4. pp. 1011-1017.
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abstract = "Two isoforms of sphingosine kinase, SK1 and SK2, catalyze the formation of the bioactive lipid sphingosine 1-phosphate (S1P) in mammalian cells. We have previously shown that treatment of androgen-sensitive LNCaP prostate cancer cells with a non-selective SK isoform inhibitor, 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi), induces the proteasomal degradation of SK1. This is concomitant with a significant increase in C22:0-ceramide and sphingosine levels and a reduction in S1P levels, resulting in the apoptosis of LNCaP cells. In contrast, we show here that a SK2-selective inhibitor, (R)-FTY720 methyl ether (ROME), increases sphingosine and decreases S1P levels but has no effect on ceramide levels and does not induce apoptosis in LNCaP cells. We also show that several glycolytic metabolites and (R)-S-lactoylglutathione are increased upon treatment of LNCaP cells with SKi, which induces the proteasomal degradation of c-Myc. These changes reflect an indirect antagonism of the Warburg effect. LNCaP cells also respond to SKi by diverting glucose 6-phosphate into the pentose phosphate pathway to provide NADPH, which serves as an antioxidant to counter an oxidative stress response. SKi also promotes the formation of a novel pro-apoptotic molecule called diadenosine 5',5'''-P(1),P(3)-triphosphate (Ap3A), which binds to the tumor suppressor fragile histidine triad protein (FHIT). In contrast, the SK2-selective inhibitor, ROME, induces a reduction in some glycolytic metabolites and does not affect oxidative stress. We conclude that SK1 functions to increase the stability of c-Myc and suppresses Ap3A formation, which might maintain the Warburg effect and cell survival, while SK2 exhibits a non-overlapping function.",
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Watson, DG, Tonelli, F, Al Osaimi, M, Williamson, L, Chan, E, Gorshkova, I, Berdyshev, E, Bittman, R, Pyne, NJ & Pyne, S 2013, 'The roles of sphingosine kinases 1 and 2 in regulating the Warburg effect in prostate cancer cells' Cellular Signalling, vol. 25, no. 4, pp. 1011-1017. https://doi.org/10.1016/j.cellsig.2013.01.002

The roles of sphingosine kinases 1 and 2 in regulating the Warburg effect in prostate cancer cells. / Watson, David G; Tonelli, Francesca; Al Osaimi, Manal; Williamson, Leon; Chan, Edmond; Gorshkova, Irina; Berdyshev, Evgeny; Bittman, Robert; Pyne, Nigel J; Pyne, Susan.

In: Cellular Signalling, Vol. 25, No. 4, 04.2013, p. 1011-1017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The roles of sphingosine kinases 1 and 2 in regulating the Warburg effect in prostate cancer cells

AU - Watson, David G

AU - Tonelli, Francesca

AU - Al Osaimi, Manal

AU - Williamson, Leon

AU - Chan, Edmond

AU - Gorshkova, Irina

AU - Berdyshev, Evgeny

AU - Bittman, Robert

AU - Pyne, Nigel J

AU - Pyne, Susan

N1 - Copyright © 2013 Elsevier Inc. All rights reserved.

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Y1 - 2013/4

N2 - Two isoforms of sphingosine kinase, SK1 and SK2, catalyze the formation of the bioactive lipid sphingosine 1-phosphate (S1P) in mammalian cells. We have previously shown that treatment of androgen-sensitive LNCaP prostate cancer cells with a non-selective SK isoform inhibitor, 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi), induces the proteasomal degradation of SK1. This is concomitant with a significant increase in C22:0-ceramide and sphingosine levels and a reduction in S1P levels, resulting in the apoptosis of LNCaP cells. In contrast, we show here that a SK2-selective inhibitor, (R)-FTY720 methyl ether (ROME), increases sphingosine and decreases S1P levels but has no effect on ceramide levels and does not induce apoptosis in LNCaP cells. We also show that several glycolytic metabolites and (R)-S-lactoylglutathione are increased upon treatment of LNCaP cells with SKi, which induces the proteasomal degradation of c-Myc. These changes reflect an indirect antagonism of the Warburg effect. LNCaP cells also respond to SKi by diverting glucose 6-phosphate into the pentose phosphate pathway to provide NADPH, which serves as an antioxidant to counter an oxidative stress response. SKi also promotes the formation of a novel pro-apoptotic molecule called diadenosine 5',5'''-P(1),P(3)-triphosphate (Ap3A), which binds to the tumor suppressor fragile histidine triad protein (FHIT). In contrast, the SK2-selective inhibitor, ROME, induces a reduction in some glycolytic metabolites and does not affect oxidative stress. We conclude that SK1 functions to increase the stability of c-Myc and suppresses Ap3A formation, which might maintain the Warburg effect and cell survival, while SK2 exhibits a non-overlapping function.

AB - Two isoforms of sphingosine kinase, SK1 and SK2, catalyze the formation of the bioactive lipid sphingosine 1-phosphate (S1P) in mammalian cells. We have previously shown that treatment of androgen-sensitive LNCaP prostate cancer cells with a non-selective SK isoform inhibitor, 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi), induces the proteasomal degradation of SK1. This is concomitant with a significant increase in C22:0-ceramide and sphingosine levels and a reduction in S1P levels, resulting in the apoptosis of LNCaP cells. In contrast, we show here that a SK2-selective inhibitor, (R)-FTY720 methyl ether (ROME), increases sphingosine and decreases S1P levels but has no effect on ceramide levels and does not induce apoptosis in LNCaP cells. We also show that several glycolytic metabolites and (R)-S-lactoylglutathione are increased upon treatment of LNCaP cells with SKi, which induces the proteasomal degradation of c-Myc. These changes reflect an indirect antagonism of the Warburg effect. LNCaP cells also respond to SKi by diverting glucose 6-phosphate into the pentose phosphate pathway to provide NADPH, which serves as an antioxidant to counter an oxidative stress response. SKi also promotes the formation of a novel pro-apoptotic molecule called diadenosine 5',5'''-P(1),P(3)-triphosphate (Ap3A), which binds to the tumor suppressor fragile histidine triad protein (FHIT). In contrast, the SK2-selective inhibitor, ROME, induces a reduction in some glycolytic metabolites and does not affect oxidative stress. We conclude that SK1 functions to increase the stability of c-Myc and suppresses Ap3A formation, which might maintain the Warburg effect and cell survival, while SK2 exhibits a non-overlapping function.

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KW - glycolysis

KW - Warburg effect

KW - oxidative stress

KW - diadenosine triphosphate

KW - cancer

KW - proteasome

KW - LNCaP metabolome

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