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FTY720 analogues as sphingosine kinase 1 inhibitors : enzyme inhibition kinetics, allosterism, proteasomal degradation and actin rearrangement in MCF-7 breast cancer cells

Lim, Keng and Tonelli, Francesca Romana and Li, Z. and Lu, X. and Bittman, R. and Pyne, Susan and Pyne, Nigel (2011) FTY720 analogues as sphingosine kinase 1 inhibitors : enzyme inhibition kinetics, allosterism, proteasomal degradation and actin rearrangement in MCF-7 breast cancer cells. Journal of Biological Chemistry, 286 (21). pp. 18633-18640. ISSN 1083-351X

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Abstract

Sphingosine kinase 1 (SK1) catalyzes the conversion of sphingosine to the bioactive lipid sphingosine 1-phosphate. We have previously demonstrated that FTY720 and (S)-FTY720 vinylphosphonate are novel inhibitors of SK1 activity. Here, we show that (S)-FTY720 vinylphosphonate binds to a putative allosteric site in SK1 contingent on formation of the enzyme-sphingosine complex. We report that SK1 is an oligomeric protein (minimally a dimer) containing noncooperative catalytic sites and that the allosteric site exerts an autoinhibition of the catalytic site. A model is proposed in which (S)-FTY720 vinylphosphonate binding to and stabilization of the allosteric site might enhance the autoinhibitory effect on SK1 activity. Further evidence for the existence of allosteric site(s) in SK1 was demonstrated by data showing that two new FTY720 analogues (a conjugate of sphingosine with a fluorophore and (S)-FTY720 regioisomer) increased SK1 activity, suggesting relief of autoinhibition of SK1 activity. Comparisons with the SK1 inhibitor, SKi or siRNA knockdown of SK1 indicated that (S)-FTY720 vinylphosphonate and FTY720 behave as typical SK1 inhibitors in preventing sphingosine 1-phosphate-stimulated rearrangement of actin in MCF-7 cells. These findings are discussed in relation to the anticancer properties of SK1 inhibitors.