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CD133 and DNA-PK regulate MDR1 via the PI3K- or Akt-NF-κB pathway in multidrug-resistant glioblastoma cells in vitro

Oncogene volume 35, pages 241–250 (2016)Cite this article

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A Retraction to this article was published on 05 September 2016

Abstract

Chemotherapy is an adjuvant treatment for glioblastomas, however, chemotherapy remains palliative because of the development of multidrug resistance (MDR). Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in recurrent glioblastomas. CD133 positive (CD133+) glioma cancer stem-like cells (GCSCs) markedly promote drug resistance and exhibit increased DNA damage repair capability; thus they have a key role in determining tumor chemosensitivity. Although CD133, DNA-dependent protein kinase (DNA-PK), and MDR1 are elevated in CD133+ GCSCs, the relationship among these molecules has not been elucidated. In this study, MDR glioblastoma cell lines were created in response to prolonged doxorubicin chemotherapy. CD133, DNA-PK and MDR1 were markedly elevated in these cells. CD133 and DNA-PK may increase MDR1 via the phosphatidylinositol-3-kinase (PI3K)-Akt signal pathway. PI3K downstream targets Akt and nuclear factor (NF)-κB, which interacts with the MDR1 promoter, were also elevated in these cells. Downregulation of CD133 and DNA-PK by small interfering RNA, or inhibition of PI3K or Akt, decreased Akt, NF-κB and MDR1 expression. The results indicate that CD133 and DNA-PK regulate MDR1 through the PI3K- or Akt-NF-κB signal pathway. Consequently, a novel chemotherapeutic regimen targeting CD133 and DNA-PK in combination with traditional protocols may increase chemotherapeutic efficacy and improve prognosis for individuals who present with glioblastoma.

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Acknowledgements

We are grateful to Dr Hao Luo for helpful suggestions and Drs Nimrod Miller and Yuping Derek Li for critical reading this article. This project was supported by the Rory David Deutsch Foundation, the Surgical Neuro-oncology Research Fund of Ann & Robert H Lurie Children’s Hospital (A&RLCH) of Chicago, and the Dr Ralph and Marian C Falk Medical Research Trust.

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Author notes

  1. S Ichi

    Present address: 5Current address: Department of Neurosurgery, Japanese Red Cross Medical Center, Shibuya-ku, Tokyo, Japan.,

  2. K Shim

    Present address: 6Current address: Department of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.,

  3. T Takao

    Present address: 7Current address: Department of Neurosurgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.,

Authors and Affiliations

  1. Division of Pediatric Neurosurgery, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA,

    G Xi, E Hayes, R Lewis, S Ichi, K Shim, T Takao, E Allender, C S Mayanil & T Tomita

  2. Falk Brain Tumor Center, Ann & Robert H Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA,

    G Xi & T Tomita

  3. Development Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA,

    S Ichi, K Shim, T Takao, E Allender & C S Mayanil

  4. Department of Biological Sciences, Purdue University Calumet, Hammond, IN, USA

    B Mania-Farnell

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Xi, G., Hayes, E., Lewis, R. et al. CD133 and DNA-PK regulate MDR1 via the PI3K- or Akt-NF-κB pathway in multidrug-resistant glioblastoma cells in vitro. Oncogene 35, 241–250 (2016). https://doi.org/10.1038/onc.2015.78

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