Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):9015-20. doi: 10.1073/pnas.1603883113. Epub 2016 Jul 22.

Combined chemical-genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma.

Author information

1
Department of Pediatrics, University of California, San Francisco, CA 94143; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143;
2
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260;
3
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143; Department of Medicine, University of California, San Francisco, CA 94143;
4
Department of Medicine, University of California, San Francisco, CA 94143;
5
Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide 5005, Australia;
6
Institute for Neurodegenerative Disease, University of California, San Francisco, CA 94143;
7
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143; Howard Hughes Medical Institute, University of California, San Francisco, CA 94143;
8
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143;
9
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260.
10
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143; Department of Medicine, University of California, San Francisco, CA 94143; trever.bivona@ucsf.edu.

Abstract

Cytosolic and organelle-based heat-shock protein (HSP) chaperones ensure proper folding and function of nascent and injured polypeptides to support cell growth. Under conditions of cellular stress, including oncogenic transformation, proteostasis components maintain homeostasis and prevent apoptosis. Although this cancer-relevant function has provided a rationale for therapeutically targeting proteostasis regulators (e.g., HSP90), cancer-subtype dependencies upon particular proteostasis components are relatively undefined. Here, we show that human rhabdomyosarcoma (RMS) cells, but not several other cancer cell types, depend upon heat-shock protein 70 kDA (HSP70) for survival. HSP70-targeted therapy (but not chemotherapeutic agents) promoted apoptosis in RMS cells by triggering an unfolded protein response (UPR) that induced PRKR-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor α (eIF2α)-CEBP homologous protein (CHOP) signaling and CHOP-mediated cell death. Intriguingly, inhibition of only cytosolic HSP70 induced the UPR, suggesting that the essential activity of HSP70 in RMS cells lies at the endoplasmic reticulum-cytosol interface. We also found that increased CHOP mRNA in clinical specimens was a biomarker for poor outcomes in chemotherapy-treated RMS patients. The data suggest that, like human epidermal growth factor receptor 2 (HER2) amplification in breast cancer, increased CHOP in RMS is a biomarker of decreased response to chemotherapy but enhanced response to targeted therapy. Our findings identify the cytosolic HSP70-UPR axis as an unexpected regulator of RMS pathogenesis, revealing HSP70-targeted therapy as a promising strategy to engage CHOP-mediated apoptosis and improve RMS treatment. Our study highlights the utility of dissecting cancer subtype-specific dependencies on proteostasis networks to uncover unanticipated cancer vulnerabilities.

KEYWORDS:

HSP70; cancer; chaperone; sarcoma; unfolded protein response

PMID:
27450084
PMCID:
PMC4987817
DOI:
10.1073/pnas.1603883113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center