Cycloheximide promotes paraptosis induced by inhibition of cyclophilins in glioblastoma multiforme

Lin Wang, Justin H. Gundelach, Richard J Bram

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Cancer is the second leading cause of death worldwide. Current treatment strategies based on multi-agent chemotherapy and/or radiation regimens have improved overall survival in some cases. However, resistance to apoptosis often develops in cancer cells, and its occurrence is thought to contribute to treatment failure. Non-apoptotic cell death mechanisms have become of great interest, therefore, in hopes that they would bypass tumor cell resistance. Glioblastoma multiforme (GBM), a grade IV astrocytic tumor is the most frequent brain tumor in adults, and has a high rate of mortality. We report that NIM811, a small molecule cyclophilin-binding inhibitor, induces catastrophic vacuolization and cell death in GBM cells. These unique features are distinct from many known cell death pathways, and are associated with an incompletely defined cell death mechanism known as paraptosis. We found that NIM811-induced paraptosis is due to unresolved ER stress. The abnormal upregulation of protein translation was responsible for the build-up of misfolded or unfolded proteins in ER, whereas pro-survival autophagy and UPR signals were shutdown during prolonged treatment with NIM811. Although cycloheximide has been claimed to suppress paraptosis, instead we find that it only temporarily delayed vacuole formation, but actually enhanced paraptotic cell death in the long term. On the other hand, mTOR inhibitors rescued cells from NIM811-induced paraptosis by sustaining autophagy and the UPR, while specifically restraining cap-dependent translation. These findings not only provide new insights into the mechanisms underlying paraptosis, but also shed light on a potential approach to enhance GBM treatment.

Original languageEnglish (US)
Pages (from-to)e2807
JournalCell death & disease
Volume8
Issue number5
DOIs
StatePublished - May 18 2017

Fingerprint

Cyclophilins
Cycloheximide
Glioblastoma
Cell Death
Autophagy
Neoplasms
Protein Unfolding
Second Primary Neoplasms
Protein Biosynthesis
Vacuoles
Treatment Failure
Brain Neoplasms
Cause of Death
Up-Regulation
Radiation
Apoptosis
Drug Therapy
Mortality
(melle-4)cyclosporin
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Cycloheximide promotes paraptosis induced by inhibition of cyclophilins in glioblastoma multiforme. / Wang, Lin; Gundelach, Justin H.; Bram, Richard J.

In: Cell death & disease, Vol. 8, No. 5, 18.05.2017, p. e2807.

Research output: Contribution to journalArticle

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