Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma

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 fou...

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Bibliographic Details
Published in:Blood 2014-09, Vol.124 (12), p.1915-1925
Main Authors: Kummetha Venkata, Jagadish, An, Ningfei, Stuart, Robert, Costa, Luciano J., Cai, Houjian, Coker, Woodrow, Song, Jin H., Gibbs, Kiwana, Matson, Terri, Garrett-Mayer, Elizabeth, Wan, Zhuang, Ogretmen, Besim, Smith, Charles, Kang, Yubin
Format: Article
Language:English
Subjects:
Adamantane - analogs & derivatives
Adamantane - pharmacology
Animals
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Caspase 3 - metabolism
Cell Line, Tumor
Cell Proliferation - drug effects
Down-Regulation - drug effects
Enzyme Inhibitors - pharmacology
Humans
Lymphoid Neoplasia
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Multiple Myeloma - drug therapy
Multiple Myeloma - enzymology
Multiple Myeloma - pathology
Myeloid Cell Leukemia Sequence 1 Protein - genetics
Myeloid Cell Leukemia Sequence 1 Protein - metabolism
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) - genetics
Proteasome Endopeptidase Complex - metabolism
Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 - metabolism
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Pyridines - pharmacology
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA, Neoplasm - genetics
RNA, Neoplasm - metabolism
RNA, Small Interfering - genetics
Xenograft Model Antitumor Assays
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Summary: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) CD138+ 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 CD138+ 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. •SK2 is overexpressed in myeloma cells and contributes to myeloma cell survival and proliferation.•SK2-specific inhibitor promotes proteasome degradation of Mcl-1 and c-Myc and inhibits myeloma growth in vitro and in vivo.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2014-03-559385