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

Abstract

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.

• Authors: Jagadish Kummetha Venkata, Ningfei An, Robert Stuart, Luciano J Costa, Houjian Cai, Woodrow Coker, Jin H Song, Kiwana Gibbs, Terri Matson, Elizabeth Garrett-Mayer, Zhuang Wan, Besim Ogretmen, Charles Smith, Yubin Kang
• Journal: Blood (Blood) Vol. 124 Issue 12 Pg. 1915-25 (Sep 18 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 25122609 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• MCL1 protein, human
• MYC protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• PMAIP1 protein, human
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc
• Pyridines
• RNA, Messenger
• RNA, Neoplasm
• RNA, Small Interfering
• 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase 2, human
• CASP3 protein, human
• Caspase 3
• Proteasome Endopeptidase Complex
• Adamantane

Topics

• Adamantane (analogs & derivatives, 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
• Mice
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Multiple Myeloma (drug therapy, enzymology, pathology)
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, genetics)
• Proteasome Endopeptidase Complex (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Pyridines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• RNA, Neoplasm (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Xenograft Model Antitumor Assays