Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts
Sphingosine 1-phosphate (S1P) is an extra- and intracellular mediator that regulates cell growth, survival, migration, and adhesion in many cell types. S1P lyase is the enzyme that irreversibly cleaves S1P and thereby constitutes the ultimate step in sphingolipid catabolism. It has been reported pre...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520356406 |
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| author | Katja Ihlefeld Hans Vienken Ralf Frederik Claas Kira Blankenbach Agnes Rudowski Michael ter Braak Alexander Koch Paul P. Van Veldhoven Josef Pfeilschifter Dagmar Meyer zu Heringdorf |
| author_facet | Katja Ihlefeld Hans Vienken Ralf Frederik Claas Kira Blankenbach Agnes Rudowski Michael ter Braak Alexander Koch Paul P. Van Veldhoven Josef Pfeilschifter Dagmar Meyer zu Heringdorf |
| author_sort | Katja Ihlefeld |
| collection | DOAJ |
| description | Sphingosine 1-phosphate (S1P) is an extra- and intracellular mediator that regulates cell growth, survival, migration, and adhesion in many cell types. S1P lyase is the enzyme that irreversibly cleaves S1P and thereby constitutes the ultimate step in sphingolipid catabolism. It has been reported previously that embryonic fibroblasts from S1P lyase-deficient mice (Sgpl1−/−-MEFs) are resistant to chemotherapy-induced apoptosis through upregulation of B cell lymphoma 2 (Bcl-2) and Bcl-2-like 1 (Bcl-xL). Here, we demonstrate that the transporter proteins Abcc1/MRP1, Abcb1/MDR1, Abca1, and spinster-2 are upregulated in Sgpl1−/−-MEFs. Furthermore, the cells efficiently sequestered the substrates of Abcc1 and Abcb1, fluo-4 and doxorubicin, in subcellular compartments. In line with this, Abcb1 was localized mainly at intracellular vesicular structures. After 16 h of incubation, wild-type MEFs had small apoptotic nuclei containing doxorubicin, whereas the nuclei of Sgpl1−/−-MEFs appeared unchanged and free of doxorubicin. A combined treatment with the inhibitors of Abcb1 and Abcc1, zosuquidar and MK571, respectively, reversed the compartmentalization of doxorubicin and rendered the cells sensitive to doxorubicin-induced apoptosis. It is concluded that upregulation of multidrug resistance transporters contributes to the chemoresistance of S1P lyase-deficient MEFs. |
| first_indexed | 2024-12-21T18:52:25Z |
| format | Article |
| id | doaj.art-f071ef55eb7d497a8e684309cb0a5c67 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-21T18:52:25Z |
| publishDate | 2015-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-f071ef55eb7d497a8e684309cb0a5c672022-12-21T18:53:42ZengElsevierJournal of Lipid Research0022-22752015-01-015616069Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblastsKatja Ihlefeld0Hans Vienken1Ralf Frederik Claas2Kira Blankenbach3Agnes Rudowski4Michael ter Braak5Alexander Koch6Paul P. Van Veldhoven7Josef Pfeilschifter8Dagmar Meyer zu Heringdorf9Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, GermanyInstitut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, GermanyInstitut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, GermanyInstitut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, GermanyInstitut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, GermanyInstitut für Pharmakologie, Universitätsklinikum Essen, Essen, GermanyInstitut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, GermanyDepartment of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, Leuven, BelgiumInstitut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, GermanyInstitut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany; To whom correspondence should be addressedSphingosine 1-phosphate (S1P) is an extra- and intracellular mediator that regulates cell growth, survival, migration, and adhesion in many cell types. S1P lyase is the enzyme that irreversibly cleaves S1P and thereby constitutes the ultimate step in sphingolipid catabolism. It has been reported previously that embryonic fibroblasts from S1P lyase-deficient mice (Sgpl1−/−-MEFs) are resistant to chemotherapy-induced apoptosis through upregulation of B cell lymphoma 2 (Bcl-2) and Bcl-2-like 1 (Bcl-xL). Here, we demonstrate that the transporter proteins Abcc1/MRP1, Abcb1/MDR1, Abca1, and spinster-2 are upregulated in Sgpl1−/−-MEFs. Furthermore, the cells efficiently sequestered the substrates of Abcc1 and Abcb1, fluo-4 and doxorubicin, in subcellular compartments. In line with this, Abcb1 was localized mainly at intracellular vesicular structures. After 16 h of incubation, wild-type MEFs had small apoptotic nuclei containing doxorubicin, whereas the nuclei of Sgpl1−/−-MEFs appeared unchanged and free of doxorubicin. A combined treatment with the inhibitors of Abcb1 and Abcc1, zosuquidar and MK571, respectively, reversed the compartmentalization of doxorubicin and rendered the cells sensitive to doxorubicin-induced apoptosis. It is concluded that upregulation of multidrug resistance transporters contributes to the chemoresistance of S1P lyase-deficient MEFs.http://www.sciencedirect.com/science/article/pii/S0022227520356406sphingolipidslysophospholipidapoptosisfluorescence microscopytransportcancer |
| spellingShingle | Katja Ihlefeld Hans Vienken Ralf Frederik Claas Kira Blankenbach Agnes Rudowski Michael ter Braak Alexander Koch Paul P. Van Veldhoven Josef Pfeilschifter Dagmar Meyer zu Heringdorf Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts Journal of Lipid Research sphingolipids lysophospholipid apoptosis fluorescence microscopy transport cancer |
| title | Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts |
| title_full | Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts |
| title_fullStr | Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts |
| title_full_unstemmed | Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts |
| title_short | Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts |
| title_sort | upregulation of abc transporters contributes to chemoresistance of sphingosine 1 phosphate lyase deficient fibroblasts |
| topic | sphingolipids lysophospholipid apoptosis fluorescence microscopy transport cancer |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520356406 |
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