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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 and Tonelli, Francesca and Leclercq, Tamara and Lim, Keng Gat and Long, Jaclyn S and Berdyshev, Evgeny and Tate, Rothwelle J and Natarajan, Viswanathan and Pitson, Stuart M and Pyne, Nigel J and Pyne, Susan (2010) The sphingosine kinase 1 inhibitor 2-(P-hydroxyanilino)-4-(P-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells. Journal of Biological Chemistry, 285 (50). pp. 38841-38852. ISSN 1083-351X

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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.

Item type: Article
ID code: 28069
Keywords: sphingosine kinase 1, pulmonary artery, breast cancer, prostate cancer, mammalian cells, Neoplasms. Tumors. Oncology (including Cancer), Therapeutics. Pharmacology, Immunology, Biochemistry, Cell Biology, Molecular Biology
Subjects: Medicine > Internal medicine > Neoplasms. Tumors. Oncology (including Cancer)
Medicine > Therapeutics. Pharmacology
Science > Microbiology > Immunology
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Related URLs:
    Depositing user: Miss Shauna Thompson
    Date Deposited: 13 Oct 2010 11:51
    Last modified: 04 Jul 2014 05:04
    URI: http://strathprints.strath.ac.uk/id/eprint/28069

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