Targeting Notch Signaling and Autophagy Increases Cytotoxicity in Glioblastoma Neurospheres

Manabu Natsumeda, Kosuke Maitani, Yang Liu, Hiroaki Miyahara, Harpreet Kaur, Qian Chu, Hongyan Zhang, Ulf D. Kahlert, Charles G. Eberhart

Research output: Contribution to journalArticle

Abstract

Glioblastomas are highly aggressive tumors that contain treatment resistant stem-like cells. Therapies targeting developmental pathways such as Notch eliminate many neoplastic glioma cells, including those with stem cell features, but their efficacy can be limited by various mechanisms. One potential avenue for chemotherapeutic resistance is the induction of autophagy, but little is known how it might modulate the response to Notch inhibitors. We used the γ-secretase inhibitor MRK003 to block Notch pathway activity in glioblastoma neurospheres and assessed its effects on autophagy. A dramatic, several fold increase of LC3B-II/LC3B-I autophagy marker was noted on western blots, along with the emergence of punctate LC3B immunostaining in cultured cells. By combining the late stage autophagy inhibitor chloroquine (CQ) with MRK003, a significant induction in apoptosis and reduction in growth was noted as compared to Notch inhibition alone. A similar beneficial effect on inhibition of cloogenicity in soft agar was seen using the combination treatment. These results demonstrated that pharmacological Notch blockade can induce protective autophagy in glioma neurospheres, resulting in chemoresistance, which can be abrogated by combination treatment with autophagy inhibitors.

Original languageEnglish (US)
Pages (from-to)713-723
Number of pages11
JournalBrain Pathology
Volume26
Issue number6
DOIs
StatePublished - Nov 1 2016

Keywords

  • autophagy
  • chloroquine
  • combination treatment
  • gamma-secretase inhibitor
  • glioblastoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)
  • Clinical Neurology

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  • Cite this

    Natsumeda, M., Maitani, K., Liu, Y., Miyahara, H., Kaur, H., Chu, Q., Zhang, H., D. Kahlert, U., & Eberhart, C. G. (2016). Targeting Notch Signaling and Autophagy Increases Cytotoxicity in Glioblastoma Neurospheres. Brain Pathology, 26(6), 713-723. https://doi.org/10.1111/bpa.12343