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Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells
Markus D Siegelin1, Takehiko Dohi, Christopher M Raskett
1Prostate Cancer Discovery and Development Program, Philadelphia, Pennsylvania, USA.
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.
Insights
Targeting heat shock protein-90 (Hsp90) in mitochondria of cancer cells initiated an organelle unfolded protein response (UPR). This UPR suppressed tumor growth and enhanced apoptosis, suggesting a novel therapeutic strategy for tumors.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Mitochondrial protein folding is crucial for cellular homeostasis and implicated in disease.
- Regulators of mitochondrial protein folding are not well understood.
Purpose of the Study:
- To investigate the role of heat shock protein-90 (Hsp90) in regulating the mitochondrial protein-folding environment in human tumor cells.
- To explore the therapeutic potential of targeting mitochondrial Hsp90.
Main Methods:
- Selective targeting of Hsp90 within mitochondria of human tumor cells.
- Analysis of compensatory autophagy and organelle unfolded protein response (UPR).
- Assessment of CCAAT enhancer binding protein (C/EBP) and NF-κB signaling pathways.
- Evaluation of tumor cell apoptosis and intracranial glioblastoma growth in mice.
Main Results:
- Targeting mitochondrial Hsp90 triggered compensatory autophagy and an organelle UPR.
- The UPR led to upregulation of C/EBP transcription factors.
- This transcriptional UPR repressed NF-κB-dependent gene expression.
- Tumor cell apoptosis was enhanced, and glioblastoma growth was inhibited in mice without toxicity.
Conclusions:
- Hsp90 chaperones play a novel role in regulating the mitochondrial protein-folding environment in tumor cells.
- Disabling this adaptive pathway represents a potential therapeutic strategy for genetically heterogeneous human tumors.
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