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Compensatory increases of select proteostasis networks after Hsp70 inhibition in cancer cells
Sara Sannino1, Christopher J Guerriero1, Amit J Sabnis2,3
1Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Abstract:
Cancer cells thrive when challenged with proteotoxic stress by inducing components of the protein folding, proteasome, autophagy and unfolded protein response (UPR) pathways. Consequently, specific molecular chaperones have been validated as targets for anti-cancer therapies. For example, inhibition of Hsp70 family proteins (hereafter Hsp70) in rhabdomyosarcoma triggers UPR induction and apoptosis. To define how these cancer cells respond to compromised proteostasis, we compared rhabdomyosarcoma cells that were sensitive (RMS13) or resistant (RMS13-R) to the Hsp70 inhibitor MAL3-101. We discovered that endoplasmic reticulum-associated degradation (ERAD) and autophagy were activated in RMS13-R cells, suggesting that resistant cells overcome Hsp70 ablation by increasing misfolded protein degradation. Indeed, RMS13-R cells degraded ERAD substrates more rapidly than RMS cells and induced the autophagy pathway. Surprisingly, inhibition of the proteasome or ERAD had no effect on RMS13-R cell survival, but silencing of select autophagy components or treatment with autophagy inhibitors restored MAL3-101 sensitivity and led to apoptosis. These data indicate a route through which cancer cells overcome a chaperone-based therapy, define how cells can adapt to Hsp70 inhibition, and demonstrate the value of combined chaperone and autophagy-based therapies.This article has an associated First Person interview with the first author of the paper.
Insights
Cancer cells resist Hsp70 inhibitor therapy by enhancing protein degradation pathways like autophagy. Combining chaperone and autophagy inhibitors can overcome this resistance, leading to apoptosis.
Area of Science:
- Cancer Biology
- Molecular Cell Biology
- Drug Discovery
Background:
- Cancer cells utilize protein homeostasis pathways to survive proteotoxic stress.
- Molecular chaperones, such as Hsp70, are validated anti-cancer targets.
- Inhibition of Hsp70 in rhabdomyosarcoma induces unfolded protein response (UPR) and apoptosis.
Purpose of the Study:
- To investigate how rhabdomyosarcoma cells adapt to Hsp70 inhibitor therapy.
- To compare proteostasis mechanisms in Hsp70 inhibitor-sensitive and resistant rhabdomyosarcoma cells.
- To identify therapeutic strategies to overcome Hsp70 inhibitor resistance.
Main Methods:
- Comparative analysis of Hsp70 inhibitor-sensitive (RMS13) and resistant (RMS13-R) rhabdomyosarcoma cells.
- Assessment of endoplasmic reticulum-associated degradation (ERAD) and autophagy pathway activation.
- Evaluation of cell survival upon inhibition or silencing of proteasome, ERAD, and autophagy components.
Main Results:
- Resistant RMS13-R cells exhibited increased ERAD substrate degradation and autophagy activation.
- Proteasome or ERAD inhibition did not affect RMS13-R cell survival.
- Autophagy inhibition or silencing restored sensitivity to Hsp70 inhibitor MAL3-101, inducing apoptosis.
Conclusions:
- Cancer cells can overcome Hsp70 inhibition by upregulating ERAD and autophagy.
- Autophagy plays a critical role in mediating resistance to Hsp70-targeted therapy.
- Combined chaperone and autophagy-based therapies may be effective in treating Hsp70 inhibitor-resistant cancers.
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