title: Stressing the ubiquitin-proteasome system without 20S proteolytic inhibition selectively kills cervical cancer cells.
abstract: Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate, and for specific signaling pathways, notably HPV E6-targeted degradation of p53 and PDZ proteins. Natural compounds with antioxidant properties including flavonoids and triterpenoids hold promise as anticancer agents by interfering with ubiquitin-dependent protein degradation. An increasing body of evidence indicates that their α-β unsaturated carbonyl system is the molecular determinant for inhibition of ubiquitin-mediated protein degradation up-stream of the catalytic sites of the 20S proteasome. Herein we report the identification and characterization of a new class of chalcone-based, potent and cell permeable chemical inhibitors of ubiquitin-dependent protein degradation, and a lead compound RAMB1. RAMB1 inhibits ubiquitin-dependent protein degradation without compromising the catalytic activities of the 20S proteasome, a mechanism distinct from that of Bortezomib. Treatment of cervical cancer cells with RAMB1 triggers unfolded protein responses, including aggresome formation and Hsp90 stabilization, and increases p53 steady state levels. RAMB1 treatment results in activation of lysosomal-dependent degradation pathways as a mechanism to compensate for increasing levels of poly-ubiquitin enriched toxic aggregates. Importantly, RAMB1 synergistically triggers cell death of cervical cancer cells when combined with the lysosome inhibitor Chloroquine.
authors: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors: Ravi K
authors: RK
authors: Anchoori
authors: Saeed R
authors: SR
authors: Khan
authors: Thanasak
authors: T
authors: Sueblinvong
authors: Alicia
authors: A
authors: Felthauser
authors: Yoshie
authors: Y
authors: Iizuka
authors: Riccardo
authors: R
authors: Gavioli
authors: Federica
authors: F
authors: Destro
authors: Rachel
authors: R
authors: Isaksson Vogel
authors: Shiwen
authors: S
authors: Peng
authors: Richard B S
authors: RB
authors: Roden
authors: Martina
authors: M
authors: Bazzaro
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D027383:Papillomaviridae / Q000187:drug effects / Q000235:genetics; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D013312:Stress, Physiological / Q000187:drug effects*; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000473:pathology* / Q000821:virology
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D061988:Proteasome Inhibitors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D025821:Polyubiquitin; D019938:Cyclin D1; D002738:Chloroquine; D046988:Proteasome Endopeptidase Complex