Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells
Markus D. Siegelin, … , Janet Plescia, Dario C. Altieri
Markus D. Siegelin, … , Janet Plescia, Dario C. Altieri
Published March 1, 2011
Citation Information: J Clin Invest. 2011;121(4):1349-1360. https://doi.org/10.1172/JCI44855.
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Research Article Oncology

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

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.

Authors

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

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Figure 4

Targeting mitochondrial Hsp90 induces organelle UPR.

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Targeting mitochondrial Hsp90 induces organelle UPR. (A) Detergent-insol...
(A) Detergent-insoluble mitochondrial proteins from control (none) or G-TPP–treated LN229 cells were visualized by silver staining. Arrowheads, insoluble, i.e., unfolded proteins. (B–E) LN229 cells were treated as indicated and analyzed by immunoblotting. SOD2, mitochondrial superoxide dismutase. (F) The indicated glioblastoma cells were transfected with control or TRAP-1–directed siRNA and analyzed by immunoblotting. (G) LN229 cells were stably transfected with control or CypD-directed shRNA and analyzed by immunoblotting. (H–I) LN229 cells were incubated with the indicated concentrations of G-TPP and analyzed by immunoblotting after 6 hours (H) or 16 hours (I). p-Akt, phosphorylated Akt; *Nonspecific.