Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors

Jie Yuan, Fan Zhang, Dennis Hallahan, Zhen Zhang, Liming He, Ling Gang Wu, Meng You, Qin Yang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background: Reprogramming of cancers into normal-like tissues is an innovative strategy for cancer treatment. Recent reports demonstrate that defined factors can reprogram cancer cells into pluripotent stem cells. Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor in humans. Despite multimodal therapy, the outcome for patients with GBM is still poor. Therefore, developing novel therapeutic strategy is a critical requirement. Methods: We have developed a novel reprogramming method that uses a conceptually unique strategy for GBM treatment. We screened a kinase inhibitor library to find which candidate inhibitors under reprogramming condition can reprogram GBM cells into neurons. The induced neurons are identified whether functional and loss of tumorigenicity. Results: We have found that mTOR and ROCK kinase inhibitors are sufficient to reprogram GBM cells into neural-like cells and "normal" neurons. The induced neurons expressed neuron-specific proteins, generated action potentials and neurotransmitter receptor-mediated currents. Genome-wide transcriptional analysis showed that the induced neurons had a profile different from GBM cells and were similar to that of control neurons induced by established methods. In vitro and in vivo tumorigenesis assays showed that induced neurons lost their proliferation ability and tumorigenicity. Moreover, reprogramming treatment with ROCK-mTOR inhibitors prevented GBM local recurrence in mice. Conclusion: This study indicates that ROCK and mTOR inhibitors-based reprogramming treatment prevents GBM local recurrence. Currently ROCK-mTOR inhibitors are used as anti-tumor drugs in patients, so this reprogramming strategy has significant potential to move rapidly toward clinical trials.

Original languageEnglish
Article number181
JournalJournal of Experimental and Clinical Cancer Research
Volume37
Issue number1
DOIs
StatePublished - Aug 2 2018

Keywords

  • GBM
  • Neuron
  • Protein kinase inhibitors
  • ROCK
  • Reprogramming
  • mTOR

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