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

Publication ,  Journal Article
Venkata, JK; An, N; Stuart, R; Costa, LJ; Cai, H; Coker, W; Song, JH; Gibbs, K; Matson, T; Garrett-Mayer, E; Wan, Z; Ogretmen, B; Smith, C; Kang, Y
Published in: Blood
September 18, 2014

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.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

September 18, 2014

Volume

124

Issue

12

Start / End Page

1915 / 1925

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • RNA, Small Interfering
  • RNA, Neoplasm
  • RNA, Messenger
  • Pyridines
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-bcl-2
  • Proteasome Endopeptidase Complex
  • Phosphotransferases (Alcohol Group Acceptor)
  • Myeloid Cell Leukemia Sequence 1 Protein
 

Citation

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Venkata, J. K., An, N., Stuart, R., Costa, L. J., Cai, H., Coker, W., … Kang, Y. (2014). Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. Blood, 124(12), 1915–1925. https://doi.org/10.1182/blood-2014-03-559385
Venkata, Jagadish Kummetha, Ningfei An, Robert Stuart, Luciano J. Costa, Houjian Cai, Woodrow Coker, Jin H. Song, et al. “Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma.Blood 124, no. 12 (September 18, 2014): 1915–25. https://doi.org/10.1182/blood-2014-03-559385.
Venkata JK, An N, Stuart R, Costa LJ, Cai H, Coker W, et al. Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. Blood. 2014 Sep 18;124(12):1915–25.
Venkata, Jagadish Kummetha, et al. “Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma.Blood, vol. 124, no. 12, Sept. 2014, pp. 1915–25. Pubmed, doi:10.1182/blood-2014-03-559385.
Venkata JK, An N, Stuart R, Costa LJ, Cai H, Coker W, Song JH, Gibbs K, Matson T, Garrett-Mayer E, Wan Z, Ogretmen B, Smith C, Kang Y. Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. Blood. 2014 Sep 18;124(12):1915–1925.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

September 18, 2014

Volume

124

Issue

12

Start / End Page

1915 / 1925

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • RNA, Small Interfering
  • RNA, Neoplasm
  • RNA, Messenger
  • Pyridines
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-bcl-2
  • Proteasome Endopeptidase Complex
  • Phosphotransferases (Alcohol Group Acceptor)
  • Myeloid Cell Leukemia Sequence 1 Protein