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PKCδ maintains phenotypes of tumor initiating cells through cytokine-mediated autocrine loop with positive feedback

Oncogene volume 34, pages 5749–5759 (2015)Cite this article

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Abstract

The existence of tumor initiating cells (TICs) has been emerged as a good therapeutic target for treatment of glioblastoma that is the most aggressive brain tumor with poor prognosis. However, the molecular mechanisms that regulate the phenotypes of TICs still remain obscure. In this study, we found that PKCδ, among PKC isoforms, is preferentially activated in TICs and acts as a critical regulator for the maintenance of TICs in glioblastoma. By modulating the expression levels or activity of PKCδ, we demonstrated that PKCδ promotes self-renewal and tumorigenic potentials of TICs. Importantly, we found that the activation of PKCδ persists in TICs through an autocrine loop with positive feedback that was driven by PKCδ/STAT3/IL-23/JAK signaling axis. Moreover, for phenotypes of TICs, we showed that PKCδ activates AKT signaling component by phosphorylation specifically on Ser473. Taken together, we proposed that TICs regulate their own population in glioblastoma through an autocrine loop with positive feedback that is driven by PKCδ-dependent secretion of cytokines.

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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 National Research Foundation (NRF) and Ministry of Science, ICT and Future Planning, Korean government, through its National Nuclear Technology Program (NRF2012M2B2B1055639 and NRF-2013M2A2A7066345).

Author Contributions

Study conception and design, collection and assembly of data, data analysis and interpretation: KR-K; study conception and design, data analysis and interpretation, manuscript writing: SY; data analysis and interpretation: HE, YK-C, CK-S, AS, HS-G, KM-J, LH-J; data analysis and interpretation, financial support: GKI; conception and design, data analysis and interpretation, financial support, final approval of manuscript: LS-J.

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  1. R-K Kim and Y Suh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Life Science, Laboratory of Molecular Biochemistry, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea

    R-K Kim, Y Suh, E Hwang, K-C Yoo, M-J Kim & S-J Lee

  2. Molecular and Cellular Imaging Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea

    K-S Choi

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

    S An

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

    S-G Hwang

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

    I-G Kim

  6. Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

    M-J Kim

  7. Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

    H-J Lee

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Kim, RK., Suh, Y., Hwang, E. et al. PKCδ maintains phenotypes of tumor initiating cells through cytokine-mediated autocrine loop with positive feedback. Oncogene 34, 5749–5759 (2015). https://doi.org/10.1038/onc.2015.29

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