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https://hdl.handle.net/2440/74153
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Type: | Journal article |
Title: | Inhibition kinetics and regulation of sphingosine kinase 1 expression in prostate cancer cells: functional differences between sphingosine kinase 1a and 1b |
Author: | Lim, K. Tonelli, F. Berdyshev, E. Gorshkova, I. Leclercq, T. Pitson, S. Bittman, R. Pyne, S. Pyne, N. |
Citation: | The International Journal of Biochemistry and Cell Biology, 2012; 44(9):1457-1464 |
Publisher: | Pergamon-Elsevier Science Ltd |
Issue Date: | 2012 |
ISSN: | 1357-2725 1878-5875 |
Statement of Responsibility: | Keng Gat Lim, Francesca Tonelli, Evgeny Berdyshev, Irina Gorshkova, Tamara Leclercq, Stuart M. Pitson, Robert Bittman, Susan Pyne and Nigel J. Pyne |
Abstract: | Sphingosine kinase 1 catalyses the formation of the bioactive lipid, sphingosine 1-phosphate and is a target for anti-cancer agents. We demonstrate here that 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi, also referred to as SKI-II), FTY720 (Fingolimod), and (S)-FTY720 vinylphosphonate inhibit sphingosine kinase 1 activity with distinct kinetics, indicating that these compounds exhibit different binding modalities with sphingosine kinase 1. Thus, SKi is a mixed inhibitor of sphingosine and ATP binding, whereas FTY720 is competitive with sphingosine and uncompetitive with ATP, and (S)-FTY720 vinylphosphonate is uncompetitive with sphingosine and is a mixed inhibitor with respect to ATP. A novel 'see-saw' model is proposed for the binding of inhibitor to catalytic and allosteric sites, the latter dependent on substrate binding, that provides an explanation for the different inhibitor kinetics. In addition, we demonstrate that the expression level and properties unique to an N-terminal 86 amino-acid isoform variant of sphingosine kinase 1 (SK1b) in prostate cancer cells reduce its sensitivity to SKi-induced proteasomal degradation in comparison to SK1a, i.e. these two N-terminal variants of sphingosine kinase 1 (SK1a and SK1b) have different properties. The reduced sensitivity of SK1b to proteasomal degradation in response to SKi is translated into specific changes in ceramide and S1P levels that leads to apoptosis of androgen-sensitive but not androgen-independent LNCaP prostate cancer cells. Therefore, our proposed 'see-saw' model might be usefully employed in the design of sphingosine kinase inhibitors to promote apoptosis of chemotherapeutic resistant cancer cells. |
Keywords: | Cell Line, Tumor Humans Prostatic Neoplasms Proteasome Endopeptidase Complex Isoenzymes Phosphotransferases (Alcohol Group Acceptor) Adenosine Triphosphate Enzyme Inhibitors Gene Expression Regulation, Neoplastic Allosteric Site Catalytic Domain Kinetics Male |
Rights: | Copyright © 2012 Elsevier B.V. All rights reserved. |
DOI: | 10.1016/j.biocel.2012.05.012 |
Published version: | http://dx.doi.org/10.1016/j.biocel.2012.05.012 |
Appears in Collections: | Aurora harvest 4 Molecular and Biomedical Science publications |
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