期刊
ONCOGENE
卷 33, 期 13, 页码 1713-1724出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.110
关键词
BAG3; autophagy; proteasome inhibitor; HDAC6; cancer
资金
- Wilhelm-Sander Stiftung
- Deutsche Krebshilfe
- Bundesministerium fur Bildung und Forschung [01GM1104C]
- Deutsche Forschungsgemeinschaft [JU 295/9-1, SPP1463, JU 295/10-2, CRU 201]
Simultaneous inhibition of the two major constitutive protein quality control (PQC) pathways, that is, the ubiquitin-proteasome system (UPS) and the aggresome-autophagy system, has been suggested as a promising strategy to trigger cell death in cancer cells. However, we observed that one third of rhabdomyosarcoma (RMS) cells survives parallel inhibition of the UPS by Bortezomib and the aggresome-autophagy pathway by the cytoplasmic histone deacetylase 6 inhibitor ST80, and is able to regrow upon drug removal, thus pointing to the induction of compensatory pathways. Here, we identify Bcl-2-associated athanogene 3 (BAG3) as a critical mediator of inducible resistance in surviving cells after concomitant blockage of constitutive PQC pathways by mitigating ST80/Bortezomib-triggered proteotoxicity via selective autophagy. ST80/Bortezomib cotreatment upregulates BAG3 mRNA and protein levels in surviving cells in addition to triggering the accumulation of insoluble protein aggregates. Intriguingly, knockdown of BAG3 by RNA interference severely impairs clearance of protein aggregates, significantly increases cell death and reduces long-term survival and clonogenic growth during recovery after ST80/Bortezomib cotreatment. Similarly, inhibition of autophagy by inducible autophagy-related protein 7 knockdown prevents removal of protein aggregates and cell regrowth during recovery after ST80/Bortezomib cotreatment. Also, the inhibition of lysosomal degradation using the V-ATPase pump inhibitor Bafilomycin A1 enhances accumulation of protein aggregates, and completely abolishes regrowth after Bortezomib/ST80-induced proteotoxic stress. By identifying BAG3 as a key mediator of inducible resistance by mitigating proteotoxicity via selective autophagy after inhibition of constitutive PQC systems, our study provides new insights into the regulation of PQC pathways in cancer cells and identifies new targets for therapeutic intervention.
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