Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells

Markus D. Siegelin, Takehiko Dohi, Christopher M. Raskett, Gregory M. Orlowski, Christine M. Powers, Candace A. Gilbert, Alonzo H. Ross, Janet Plescia, Dario C. Altieri

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

Fine tuning of the protein folding environment in subcellular organelles, such as mitochondria, is important for adaptive homeostasis and may participate in human diseases, but the regulators of this process are still largely elusive. Here, we have shown that selective targeting of heat shock protein-90 (Hsp90) chaperones in mitochondria of human tumor cells triggered compensatory autophagy and an organelle unfolded protein response (UPR) centered on upregulation of CCAAT enhancer binding protein (C/EBP) transcription factors. In turn, this transcriptional UPR repressed NF-κB-dependent gene expression, enhanced tumor cell apoptosis initiated by death receptor ligation, and inhibited intracranial glioblastoma growth in mice without detectable toxicity. These data reveal what we believe to be a novel role of Hsp90 chaperones in the regulation of the protein-folding environment in mitochondria of tumor cells. Disabling this general adaptive pathway could potentially be used in treatment of genetically heterogeneous human tumors.

Original languageEnglish (US)
Pages (from-to)1349-1360
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number4
DOIs
StatePublished - Apr 1 2011

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Siegelin, M. D., Dohi, T., Raskett, C. M., Orlowski, G. M., Powers, C. M., Gilbert, C. A., Ross, A. H., Plescia, J., & Altieri, D. C. (2011). Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. Journal of Clinical Investigation, 121(4), 1349-1360. https://doi.org/10.1172/JCI44855