title: Combined inhibition of Hsp90 and the proteasome affects NSCLC proteostasis and attenuates cell migration.
abstract: Lung cancer remains the most common cause of cancer-related death worldwide. This malignancy is a complex disease, and it is important to identify potential biological targets, the blockade of which would affect multiple downstream signaling cascades. A growing number of reports recognize novel therapeutic targets in the protein homeostasis network responsible for generating and protecting the protein fold. The heat shock protein 90 (Hsp90) is an essential molecular chaperon involved in the posttranslational folding and stability of proteins. It is required for conformational maturation of multiple oncogenic kinases that drive signal transduction and proliferation of cancer cells. However, in the case of unfolded protein accumulation endoplasmic reticulum (ER) stress is induced and several response pathways such as proteasome functions are activated. The ubiquitin-proteasome system orchestrates the turnover of innumerable cellular proteins. Here, we suggest that the therapeutic efficacy of Hsp90 inhibition may be augmented by coadministering proteasome inhibitor on human non-small-cell lung cancer (NSCLC) cell lines. Indeed, we showed that coadministration of the Hsp90 inhibitor 17-demethoxygeldanamycin (17-DMAG) and proteasome inhibitor (velcade) induced ER stress evidenced by increased unfolded protein response markers. The consequences were evident in multiple aspects of the NSCLC phenotype: reduced viability and cell count, increased apoptotic cell death, and most profoundly, synergistically decreased cell motility. Our findings provide proof-of-concept that targeting ER homeostasis is therapeutically beneficial in NSCLC cell lines.
authors.affiliation: aLung Cancer Research Laboratory bOncogenetic Laboratory cOncology Department, Lung Cancer Unit, Meir Medical Center, Kfar Saba dSackler Faculty of Medicine, Tel Aviv University Ramat Aviv, Tel Aviv, Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Zismanov
authors.forename: Liat
authors.initials: L
authors.lastname: Drucker
authors.forename: Maya
authors.initials: M
authors.lastname: Gottfried
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D061988:Proteasome Inhibitors; D011719:Pyrazines; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex