Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis[S]
Sphingolipids (SLs) have been implicated in numerous important cellular biologies; however, their study has been hindered by the complexities of SL metabolism. Furthermore, enzymes of SL metabolism represent a dynamic and interconnected network in which one metabolite can be transformed into other b...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-04-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520325955 |
| _version_ | 1818691062925885440 |
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| author | Justin M. Snider Magali Trayssac Christopher J. Clarke Nicholas Schwartz Ashley J. Snider Lina M. Obeid Chiara Luberto Yusuf A. Hannun |
| author_facet | Justin M. Snider Magali Trayssac Christopher J. Clarke Nicholas Schwartz Ashley J. Snider Lina M. Obeid Chiara Luberto Yusuf A. Hannun |
| author_sort | Justin M. Snider |
| collection | DOAJ |
| description | Sphingolipids (SLs) have been implicated in numerous important cellular biologies; however, their study has been hindered by the complexities of SL metabolism. Furthermore, enzymes of SL metabolism represent a dynamic and interconnected network in which one metabolite can be transformed into other bioactive SLs through further metabolism, resulting in diverse cellular responses. Here we explore the effects of both lethal and sublethal doses of doxorubicin (Dox) in MCF-7 cells. The two concentrations of Dox resulted in the regulation of SLs, including accumulations in sphingosine, sphingosine-1-phosphate, dihydroceramide, and ceramide, as well as reduced levels of hexosylceramide. To further define the effects of Dox on SLs, metabolic flux experiments utilizing a d17 dihydrosphingosine probe were conducted. Results indicated the regulation of ceramidases and sphingomyelin synthase components specifically in response to the cytostatic dose. The results also unexpectedly demonstrated dose-dependent inhibition of dihydroceramide desaturase and glucosylceramide synthase in response to Dox. Taken together, this study uncovers novel targets in the SL network for the action of Dox, and the results reveal the significant complexity of SL response to even a single agent. This approach helps to define the role of specific SL enzymes, their metabolic products, and the resulting biologies in response to chemotherapeutics and other stimuli. |
| first_indexed | 2024-12-17T12:35:56Z |
| format | Article |
| id | doaj.art-edd658a4fb7544ca9558d503d8777bf8 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T12:35:56Z |
| publishDate | 2019-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-edd658a4fb7544ca9558d503d8777bf82022-12-21T21:48:18ZengElsevierJournal of Lipid Research0022-22752019-04-01604819831Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis[S]Justin M. Snider0Magali Trayssac1Christopher J. Clarke2Nicholas Schwartz3Ashley J. Snider4Lina M. Obeid5Chiara Luberto6Yusuf A. Hannun7Molecular and Cellular Biology and Biochemistry and Structural Biology Graduate Program, Stony Brook University, Stony Brook, NY; Departments of Medicine, Stony Brook University, Stony Brook, NY; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NYDepartments of Medicine, Stony Brook University, Stony Brook, NY; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NYDepartments of Medicine, Stony Brook University, Stony Brook, NY; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NYDepartments of Medicine, Stony Brook University, Stony Brook, NY; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NYDepartments of Medicine, Stony Brook University, Stony Brook, NY; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY; Northport Veterans Affairs Medical Center, Northport, NYDepartments of Medicine, Stony Brook University, Stony Brook, NY; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY; Northport Veterans Affairs Medical Center, Northport, NYTo whom correspondence should be addressed. (Y.A.H.); (C.L.); Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY; Departments of Physiology and Biophysics, Stony Brook University, Stony Brook, NY; To whom correspondence should be addressed. (Y.A.H.); (C.L.)To whom correspondence should be addressed. (Y.A.H.); (C.L.); Departments of Medicine, Stony Brook University, Stony Brook, NY; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY; Departments of Biochemistry, Stony Brook University, Stony Brook, NY; Departments of Pharmacology, Stony Brook University, Stony Brook, NY; Departments of Pathology, Stony Brook University, Stony Brook, NY; To whom correspondence should be addressed. (Y.A.H.); (C.L.)Sphingolipids (SLs) have been implicated in numerous important cellular biologies; however, their study has been hindered by the complexities of SL metabolism. Furthermore, enzymes of SL metabolism represent a dynamic and interconnected network in which one metabolite can be transformed into other bioactive SLs through further metabolism, resulting in diverse cellular responses. Here we explore the effects of both lethal and sublethal doses of doxorubicin (Dox) in MCF-7 cells. The two concentrations of Dox resulted in the regulation of SLs, including accumulations in sphingosine, sphingosine-1-phosphate, dihydroceramide, and ceramide, as well as reduced levels of hexosylceramide. To further define the effects of Dox on SLs, metabolic flux experiments utilizing a d17 dihydrosphingosine probe were conducted. Results indicated the regulation of ceramidases and sphingomyelin synthase components specifically in response to the cytostatic dose. The results also unexpectedly demonstrated dose-dependent inhibition of dihydroceramide desaturase and glucosylceramide synthase in response to Dox. Taken together, this study uncovers novel targets in the SL network for the action of Dox, and the results reveal the significant complexity of SL response to even a single agent. This approach helps to define the role of specific SL enzymes, their metabolic products, and the resulting biologies in response to chemotherapeutics and other stimuli.http://www.sciencedirect.com/science/article/pii/S0022227520325955high-performance liquid chromatography-electrospray ionization-tandem mass spectrometrychemotherapeuticmetabolism |
| spellingShingle | Justin M. Snider Magali Trayssac Christopher J. Clarke Nicholas Schwartz Ashley J. Snider Lina M. Obeid Chiara Luberto Yusuf A. Hannun Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis[S] Journal of Lipid Research high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry chemotherapeutic metabolism |
| title | Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis[S] |
| title_full | Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis[S] |
| title_fullStr | Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis[S] |
| title_full_unstemmed | Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis[S] |
| title_short | Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis[S] |
| title_sort | multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis s |
| topic | high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry chemotherapeutic metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520325955 |
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