The sphingosine kinase 1 inhibitor 2-(P-hydroxyanilino)-4-(P-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells

Carolyn Loveridge, Francesca Tonelli, Tamara Leclercq, Keng Gat Lim, Jaclyn S Long, Evgeny Berdyshev, Rothwelle J Tate, Viswanathan Natarajan, Stuart M Pitson, Nigel J Pyne, Susan Pyne

Research output: Contribution to journalArticle

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Abstract

Sphingosine kinase 1 (SK1) is an enzyme that catalyses the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of SK1 in human pulmonary artery smooth muscle cells, androgen-sensitive LNCaP prostate cancer cells, MCF-7 and MCF-7 HER2 breast cancer cells and that this is likely mediated by ceramide as a consequence of catalytic inhibition of SK1 by SKi. Moreover, SK1 is polyubiquitinated under basal conditions, and SKi appears to increase the degradation of SK1 by activating the proteasome. In addition, the proteasomal degradation of SK1a and SK1b in androgen-sensitive LNCaP cells is associated with the induction of apoptosis. However, SK1b in LNCaP-AI cells (androgen-independent) is less sensitive to SKi-induced proteasomal degradation and these cells are resistant to SKi-induced apoptosis, thereby highlighting the ubiquitin-proteasomal degradation of SK1 as an important mechanism controlling cell survival.
LanguageEnglish
Pages38841-38852
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number50
DOIs
Publication statusPublished - 10 Dec 2010

Fingerprint

Thiazoles
Cells
Degradation
Androgens
Apoptosis
Phosphorylation
Sphingosine
Ceramides
MCF-7 Cells
Proteasome Endopeptidase Complex
Ubiquitin
sphingosine kinase
Pulmonary Artery
Smooth Muscle Myocytes
Muscle
Prostatic Neoplasms
Cell Survival
Breast Neoplasms
Lipids
Enzymes

Keywords

  • sphingosine kinase 1
  • pulmonary artery
  • breast cancer
  • prostate cancer
  • mammalian cells

Cite this

Loveridge, Carolyn ; Tonelli, Francesca ; Leclercq, Tamara ; Lim, Keng Gat ; Long, Jaclyn S ; Berdyshev, Evgeny ; Tate, Rothwelle J ; Natarajan, Viswanathan ; Pitson, Stuart M ; Pyne, Nigel J ; Pyne, Susan. / The sphingosine kinase 1 inhibitor 2-(P-hydroxyanilino)-4-(P-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells. In: Journal of Biological Chemistry . 2010 ; Vol. 285, No. 50. pp. 38841-38852.
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abstract = "Sphingosine kinase 1 (SK1) is an enzyme that catalyses the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of SK1 in human pulmonary artery smooth muscle cells, androgen-sensitive LNCaP prostate cancer cells, MCF-7 and MCF-7 HER2 breast cancer cells and that this is likely mediated by ceramide as a consequence of catalytic inhibition of SK1 by SKi. Moreover, SK1 is polyubiquitinated under basal conditions, and SKi appears to increase the degradation of SK1 by activating the proteasome. In addition, the proteasomal degradation of SK1a and SK1b in androgen-sensitive LNCaP cells is associated with the induction of apoptosis. However, SK1b in LNCaP-AI cells (androgen-independent) is less sensitive to SKi-induced proteasomal degradation and these cells are resistant to SKi-induced apoptosis, thereby highlighting the ubiquitin-proteasomal degradation of SK1 as an important mechanism controlling cell survival.",
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The sphingosine kinase 1 inhibitor 2-(P-hydroxyanilino)-4-(P-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells. / Loveridge, Carolyn; Tonelli, Francesca; Leclercq, Tamara; Lim, Keng Gat; Long, Jaclyn S; Berdyshev, Evgeny; Tate, Rothwelle J; Natarajan, Viswanathan; Pitson, Stuart M; Pyne, Nigel J; Pyne, Susan.

In: Journal of Biological Chemistry , Vol. 285, No. 50, 10.12.2010, p. 38841-38852.

Research output: Contribution to journalArticle

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T1 - The sphingosine kinase 1 inhibitor 2-(P-hydroxyanilino)-4-(P-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells

AU - Loveridge, Carolyn

AU - Tonelli, Francesca

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AU - Lim, Keng Gat

AU - Long, Jaclyn S

AU - Berdyshev, Evgeny

AU - Tate, Rothwelle J

AU - Natarajan, Viswanathan

AU - Pitson, Stuart M

AU - Pyne, Nigel J

AU - Pyne, Susan

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