C-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

C. H. Yoon, M. J. Kim, R. K. Kim, E. J. Lim, K. S. Choi, S. An, S. G. Hwang, Seok-Gu Kang, Y. Suh, M. J. Park, S. J. Lee

Research output: Contribution to journalArticle

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Abstract

Uncovering the mechanisms that govern the maintenance of stem-like cancer cells is critical for developing therapeutic strategies for targeting these cells. Constitutive activation of c-Jun N-terminal kinase (JNK) has been reported in gliomas and correlates with histological grade. Here, we found that JNK signaling is crucial for the maintenance of stemness in glioma cells. Sphere-cultured glioma cells showed more phosphorylation of JNK compared with serum-containing monolayer cultures. Importantly, blockade of JNK signaling with SP600125 or small interfering RNAs targeting JNK1 or JNK2 significantly reduced the CD133/Nestin population and suppressed sphere formation, colony formation in soft agar, and expression of stem cell markers in sphere-cultured glioma cells. Intriguingly, sphere-cultured glioma cells exhibited enhanced expression of Notch-2, but not Notch-1,-3 or-4, and JNK inhibition almost completely abrogated this increase. Blocking the phosphoinoside 3-kinase (PI3K)/Akt pathway with LY294002 or si-Akt also suppressed the self-renewal of sphere-cultured glioma cells. PI3K, but not Akt, had a role as an upstream kinase in JNK1/2 activation. In addition, treatment with si-JNK greatly increased etoposide-and ionizing radiation (IR)-induced cell death in glioma spheres. Consistent with glioma cell lines, glioma stem-like cells isolated from primary patient glioma cells also had a higher activity of JNK and Notch-2 expression. Importantly, inhibition of JNK2 led to a decrease of Notch-2 expression and suppressed the CD133/Nestin cell population in patient-derived primary glioma cells. Finally, downregulation of JNK2 almost completely suppressed intracranial tumor formation by glioma cells in nude mice. Taken together, these data demonstrate that JNK signaling is crucial for the maintenance of self-renewal and tumorigenicity of glioma stem-like cells and drug/IR resistance, and can be considered a promising target for eliminating stem-like cancer cells in gliomas.

Original languageEnglish
Pages (from-to)4655-4666
Number of pages12
JournalOncogene
Volume31
Issue number44
DOIs
Publication statusPublished - 2012 Nov 1

Fingerprint

Glioma
Phosphotransferases
Stem Cells
JNK Mitogen-Activated Protein Kinases
Cultured Cells
Nestin
Neoplastic Stem Cells
Ionizing Radiation
Mitogen-Activated Protein Kinase 9
Mitogen-Activated Protein Kinase 8
Maintenance
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Etoposide
Nude Mice
Small Interfering RNA
Population
Agar
Cell Death
Down-Regulation
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Yoon, C. H., Kim, M. J., Kim, R. K., Lim, E. J., Choi, K. S., An, S., ... Lee, S. J. (2012). C-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells. Oncogene, 31(44), 4655-4666. https://doi.org/10.1038/onc.2011.634
Yoon, C. H. ; Kim, M. J. ; Kim, R. K. ; Lim, E. J. ; Choi, K. S. ; An, S. ; Hwang, S. G. ; Kang, Seok-Gu ; Suh, Y. ; Park, M. J. ; Lee, S. J. / C-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells. In: Oncogene. 2012 ; Vol. 31, No. 44. pp. 4655-4666.
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Yoon, CH, Kim, MJ, Kim, RK, Lim, EJ, Choi, KS, An, S, Hwang, SG, Kang, S-G, Suh, Y, Park, MJ & Lee, SJ 2012, 'C-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells', Oncogene, vol. 31, no. 44, pp. 4655-4666. https://doi.org/10.1038/onc.2011.634

C-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells. / Yoon, C. H.; Kim, M. J.; Kim, R. K.; Lim, E. J.; Choi, K. S.; An, S.; Hwang, S. G.; Kang, Seok-Gu; Suh, Y.; Park, M. J.; Lee, S. J.

In: Oncogene, Vol. 31, No. 44, 01.11.2012, p. 4655-4666.

Research output: Contribution to journalArticle

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T1 - C-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

AU - Yoon, C. H.

AU - Kim, M. J.

AU - Kim, R. K.

AU - Lim, E. J.

AU - Choi, K. S.

AU - An, S.

AU - Hwang, S. G.

AU - Kang, Seok-Gu

AU - Suh, Y.

AU - Park, M. J.

AU - Lee, S. J.

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N2 - Uncovering the mechanisms that govern the maintenance of stem-like cancer cells is critical for developing therapeutic strategies for targeting these cells. Constitutive activation of c-Jun N-terminal kinase (JNK) has been reported in gliomas and correlates with histological grade. Here, we found that JNK signaling is crucial for the maintenance of stemness in glioma cells. Sphere-cultured glioma cells showed more phosphorylation of JNK compared with serum-containing monolayer cultures. Importantly, blockade of JNK signaling with SP600125 or small interfering RNAs targeting JNK1 or JNK2 significantly reduced the CD133/Nestin population and suppressed sphere formation, colony formation in soft agar, and expression of stem cell markers in sphere-cultured glioma cells. Intriguingly, sphere-cultured glioma cells exhibited enhanced expression of Notch-2, but not Notch-1,-3 or-4, and JNK inhibition almost completely abrogated this increase. Blocking the phosphoinoside 3-kinase (PI3K)/Akt pathway with LY294002 or si-Akt also suppressed the self-renewal of sphere-cultured glioma cells. PI3K, but not Akt, had a role as an upstream kinase in JNK1/2 activation. In addition, treatment with si-JNK greatly increased etoposide-and ionizing radiation (IR)-induced cell death in glioma spheres. Consistent with glioma cell lines, glioma stem-like cells isolated from primary patient glioma cells also had a higher activity of JNK and Notch-2 expression. Importantly, inhibition of JNK2 led to a decrease of Notch-2 expression and suppressed the CD133/Nestin cell population in patient-derived primary glioma cells. Finally, downregulation of JNK2 almost completely suppressed intracranial tumor formation by glioma cells in nude mice. Taken together, these data demonstrate that JNK signaling is crucial for the maintenance of self-renewal and tumorigenicity of glioma stem-like cells and drug/IR resistance, and can be considered a promising target for eliminating stem-like cancer cells in gliomas.

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