Molecular crosstalk between the proteasome, aggresomes and autophagy: translational potential and clinical implications.
Targeting the ubiquitin+proteasome protein degradation pathway with the therapeutic agent bortezomib has significantly improved the survival of cancer patients but drug resistance inevitably develops. Aggresomes and the autophagy pathway serve as compensatory protein-clearance mechanisms that eradicate potentially toxic proteins to promote resistance to proteasome inhibitors and, hence, tumor survival. Pre-clinical evidence has emerged to demonstrate active crosstalk between these protein degradation pathways and has revealed novel therapeutic targets and strategies. Translational research and clinical trials are now focused on these pathways to prevent the emergence of drug resistance, enhance apoptosis and further improve the survival of cancer patients.
The Vontz Center for Molecular Studies, University of Cincinnati, OH 45267-0508, United States. driscojs@uc.edu
James J
JJ
Driscoll
Roopa De
RD
Chowdhury
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D002738:Chloroquine / Q000494:pharmacology; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005544:Forecasting; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D008495:Medical Oncology; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors; D059748:Proteolysis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D057170:Translational Research, Biomedical; D025801:Ubiquitin / Q000502:physiology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D025801:Ubiquitin; C025946:3-methyladenine; D000069286:Bortezomib; D002738:Chloroquine; D046988:Proteasome Endopeptidase Complex; D000225:Adenine