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

Oncogene volume 31, pages 4655–4666 (2012)Cite this article

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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.

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Acknowledgements

We thank Dr Akio Soeda (Department of Neurological Surgery, University of Virginia, USA) for providing patient-derived glioma cells. This work was supported by the Korea Research Foundation (KRF) and Ministry of Education, Science and Technology (MEST), Korean government, through its National Nuclear Technology Program (2008-2003935) and the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea (1020340).

Author contributions: Chang-Hwan Yoon and Min-Jung Kim helped in the collection and assembly of data, data analysis and interpretation. Rae-Kwon Kim and Eun-Jung Lim helped in collection of data. Kyu-Sil Choi, Sungkwan An, Sang-Gu Hwang and Kang Seok-Gu helped in data analysis and interpretation. Yongjoon Suh helped in data analysis and interpretation, manuscript writing. Myung-Jin Parkhelped in manuscript writing, data analysis and interpretation, provision of study material or patients. Su-Jae Lee helped in conception and design, manuscript writing, data analysis and interpretation, final approval of manuscript.

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Authors and Affiliations

  1. Department of Chemistry, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea

    C-H Yoon, R-K Kim, E-J Lim, Y Suh & S-J Lee

  2. Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, Republic of Korea

    M-J Kim

  3. Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea

    K-S Choi

  4. Functional Genoproteome Research Centre, Konkuk University, Seoul, Korea

    S An

  5. Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

    S-G Hwang & M-J Park

  6. Department of Neurosurgery, Seoul St Mary's Hospital, Catholic University, Seoul, Korea

    S-G Kang

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  1. C-H Yoon
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Yoon, CH., Kim, MJ., Kim, RK. et al. c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells. Oncogene 31, 4655–4666 (2012). https://doi.org/10.1038/onc.2011.634

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