Cyclophilin B supports MYC and mutant p53-dependent survival of glioblastoma multiforme cells

Jae Won Choi, Mark A. Schroeder, Jann N Sarkaria, Richard J Bram

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Glioblastoma multiforme is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here, we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in glioblastoma multiforme cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human glioblastoma multiforme cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of glioblastoma multiforme cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-mitogen-activated protein kinase pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1, and Janus-activated kinase/STAT3 signaling. Elevated reactive oxygen species, ER expansion, and abnormal unfolded protein responses in CypB-depleted glioblastoma multiforme cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of glioblastoma multiforme tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for glioblastoma multiforme therapy.

Original languageEnglish (US)
Pages (from-to)484-496
Number of pages13
JournalCancer Research
Volume74
Issue number2
DOIs
StatePublished - Jan 15 2014

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Glioblastoma
Survival
Endoplasmic Reticulum
Cell Survival
Peptidylprolyl Isomerase
Cyclophilins
Janus Kinases
Unfolded Protein Response
Endoplasmic Reticulum Stress
cyclophilin B
Cell Aging
Protein Folding
Mitogen-Activated Protein Kinases
Brain Neoplasms
Glioma
Cyclosporine
Reactive Oxygen Species
Cell Proliferation
Databases
Gene Expression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cyclophilin B supports MYC and mutant p53-dependent survival of glioblastoma multiforme cells. / Choi, Jae Won; Schroeder, Mark A.; Sarkaria, Jann N; Bram, Richard J.

In: Cancer Research, Vol. 74, No. 2, 15.01.2014, p. 484-496.

Research output: Contribution to journalArticle

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