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

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105 Citations (Scopus)


Sphingosine kinase 1 (SK1) is an enzyme that catalyzes 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 implicating the ubiquitin-proteasomal degradation of SK1 as an important mechanism controlling cell survival.

Original languageEnglish
Pages (from-to)38841-38852
Number of pages12
JournalJournal of Biological Chemistry
Issue number50
Publication statusPublished or Issued - 10 Dec 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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