Shamshiddinova, M.; Gulyamov, S.; Kim, H.-J.; Jung, S.-H.; Baek, D.-J.; Lee, Y.-M. A Dansyl-Modified Sphingosine Kinase Inhibitor DPF-543 Enhanced De Novo Ceramide Generation. Int. J. Mol. Sci.2021, 22, 9190.
Shamshiddinova, M.; Gulyamov, S.; Kim, H.-J.; Jung, S.-H.; Baek, D.-J.; Lee, Y.-M. A Dansyl-Modified Sphingosine Kinase Inhibitor DPF-543 Enhanced De Novo Ceramide Generation. Int. J. Mol. Sci. 2021, 22, 9190.
Shamshiddinova, M.; Gulyamov, S.; Kim, H.-J.; Jung, S.-H.; Baek, D.-J.; Lee, Y.-M. A Dansyl-Modified Sphingosine Kinase Inhibitor DPF-543 Enhanced De Novo Ceramide Generation. Int. J. Mol. Sci.2021, 22, 9190.
Shamshiddinova, M.; Gulyamov, S.; Kim, H.-J.; Jung, S.-H.; Baek, D.-J.; Lee, Y.-M. A Dansyl-Modified Sphingosine Kinase Inhibitor DPF-543 Enhanced De Novo Ceramide Generation. Int. J. Mol. Sci. 2021, 22, 9190.
Abstract
Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P was linked to the pathological outcome with inflammation, cancer metastasis or angiogenesis etc. In this regard, the SPHK/S1P axis regulation has been a specific issue in anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhance the serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs which eventually induced an unusual environment of the high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase) that contributes a partial increase on Cers. Collectively, a dansyl-modified DPF-543 relatively en-hanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.
Chemistry and Materials Science, Analytical Chemistry
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