Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma
| Autor: | Elizabeth Garrett-Mayer, Robert K. Stuart, Luciano J. Costa, Jagadish Kummetha Venkata, Kiwana Gibbs, Woodrow J. Coker, Besim Ogretmen, Jin H. Song, Yubin Kang, Zhuang Wan, Houjian Cai, Terri Matson, Ningfei An, Charles D. Smith |
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| Rok vydání: | 2014 |
| Předmět: |
Proteasome Endopeptidase Complex
Pathology medicine.medical_specialty Stromal cell Pyridines Immunology Cell Down-Regulation Adamantane Antineoplastic Agents Apoptosis Mice SCID Biology Biochemistry Proto-Oncogene Proteins c-myc Mice chemistry.chemical_compound Mice Inbred NOD immune system diseases Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans RNA Messenger RNA Neoplasm Enzyme Inhibitors RNA Small Interfering Multiple myeloma Cell Proliferation Mice Knockout Lymphoid Neoplasia Sphingosine Caspase 3 Cell growth Sphingosine Kinase 2 Cell Biology Hematology medicine.disease Xenograft Model Antitumor Assays Phosphotransferases (Alcohol Group Acceptor) medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 chemistry Cancer cell Cancer research Myeloid Cell Leukemia Sequence 1 Protein Multiple Myeloma |
| Zdroj: | Blood. 124:1915-1925 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2014-03-559385 |
| Popis: | Sphingolipid metabolism is being increasingly recognized as a key pathway in regulating cancer cell survival and proliferation. However, very little is known about its role in multiple myeloma (MM). We investigated the potential of targeting sphingosine kinase 2 (SK2) for the treatment of MM. We found that SK2 was overexpressed in MM cell lines and in primary human bone marrow (BM) CD1381 myeloma cells. Inhibition of SK2 by SK2- specific short hairpin RNA or ABC294640 (a SK2 specific inhibitor) effectively inhibited myeloma cell proliferation and induced caspase 3–mediated apoptosis. ABC294640 inhibited primary human CD1381 myeloma cells with the same efficacy as with MM cell lines. ABC294640 effectively induced apoptosis of myeloma cells, even in the presence of BM stromal cells. Furthermore, we found that ABC294640 downregulated the expression of pS6 and directed c-Myc and myeloid cell leukemia 1 (Mcl-1) for proteasome degradation. In addition, ABC294640 increased Noxa gene transcription and protein expression. ABC294640, per se, did not affect the expression of B-cell lymphoma 2 (Bcl-2), but acted synergistically with ABT-737 (a Bcl-2 inhibitor) in inducing myeloma cell death. ABC294640 suppressed myeloma tumor growth in vivo in mouse myeloma xenograft models. Our data demonstrated that SK2 provides a novel therapeutic target for the treatment of MM.This trial was registered at www.clinicaltrials.gov as #NCT01410981. |
| Databáze: | OpenAIRE |
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