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

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

Research output: Contribution to journalArticle

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Abstract

Sphingolipid metabolismisbeing increasingly recognized as a key path way 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, eveninthe 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 lymphoma2(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.

Original languageEnglish (US)
Pages (from-to)1915-1925
Number of pages11
JournalBlood
Volume124
Issue number12
DOIs
StatePublished - Sep 18 2014

Fingerprint

Myeloid Leukemia
Myeloid Cells
Multiple Myeloma
Down-Regulation
Apoptosis
Cells
Bone
B-Lymphocytes
Cell Proliferation
Noxae
Cell Line
Sphingolipids
Cell proliferation
Cell death
Proteasome Endopeptidase Complex
Transcription
3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
sphingosine kinase
Mesenchymal Stromal Cells
Heterografts

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Venkata, Jagadish Kummetha ; 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. / Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. In: Blood. 2014 ; Vol. 124, No. 12. pp. 1915-1925.
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title = "Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma",
abstract = "Sphingolipid metabolismisbeing increasingly recognized as a key path way 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, eveninthe 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 lymphoma2(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.",
author = "Venkata, {Jagadish Kummetha} and Ningfei An and Robert Stuart and Costa, {Luciano J.} and Houjian Cai and Woodrow Coker and Song, {Jin H.} and Kiwana Gibbs and Terri Matson and Elizabeth Garrett-Mayer and Zhuang Wan and Besim Ogretmen and Charles Smith and Yubin Kang",
year = "2014",
month = "9",
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doi = "10.1182/blood-2014-03-559385",
language = "English (US)",
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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 2014, '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, pp. 1915-1925. https://doi.org/10.1182/blood-2014-03-559385

Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. / Venkata, Jagadish Kummetha; 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.

In: Blood, Vol. 124, No. 12, 18.09.2014, p. 1915-1925.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma

AU - Venkata, Jagadish Kummetha

AU - An, Ningfei

AU - Stuart, Robert

AU - Costa, Luciano J.

AU - Cai, Houjian

AU - Coker, Woodrow

AU - Song, Jin H.

AU - Gibbs, Kiwana

AU - Matson, Terri

AU - Garrett-Mayer, Elizabeth

AU - Wan, Zhuang

AU - Ogretmen, Besim

AU - Smith, Charles

AU - Kang, Yubin

PY - 2014/9/18

Y1 - 2014/9/18

N2 - Sphingolipid metabolismisbeing increasingly recognized as a key path way 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, eveninthe 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 lymphoma2(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.

AB - Sphingolipid metabolismisbeing increasingly recognized as a key path way 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, eveninthe 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 lymphoma2(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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