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Type: Journal article
Title: Combined chemical-genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma
Author: Sabnis, A.
Guerriero, C.
Olivas, V.
Sayana, A.
Shue, J.
Flanagan, J.
Asthan, S.
Patone, A.
Paton, J.
Gestwicki, J.
Walter, P.
Weissman, J.
Wip, P.
Brodsky, J.
Bivon, T.
Citation: Proceedings of the National Academy of Sciences of the United States of America, 2016; 113(32):9015-9020
Publisher: National Academy of Sciences
Issue Date: 2016
ISSN: 0027-8424
Statement of
Amit J. Sabnis, Christopher J. Guerriero, Victor Olivas, Anin Sayana, Jonathan Shue, Jennifer Flanagan, Saurabh Asthana, Adrienne W. Patone, James C. Paton, Jason E. Gestwicki, Peter Walter, Jonathan S. Weissman, Peter Wipf, Jeffrey L. Brodsky and Trever G. Bivona
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
Rights: Copyright status unknown
RMID: 0030051343
DOI: 10.1073/pnas.1603883113
Appears in Collections:Microbiology and Immunology publications

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