title: Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells.
abstract: Breast cancer is one of the leading causes of cancer death among women in the United States. Patients expressing the estrogen and progesterone receptor (ER and PR) and human epidermal growth factor 2 (HER-2) tumor markers have favorable prognosis and efficacious therapeutic options. In contrast, tumors that are negative for these markers (triple-negative) have a disproportionate share of morbidity and mortality due to lack of a validated molecular target. Deubiquitinating enzymes (DUBs) are a critical component of ubiquitin-proteasome-system degradation and have been shown to be differentially expressed and activated in a number of cancers, including breast, with their aberrant activity linked to cancer prognosis and clinical outcome. We evaluated the effect of the DUB inhibitors b-AP15 and RA-9 alone and in combination with early- and late-stage lysosomal inhibitors on cell viability in a panel of triple negative breast cancer (TNBC) cell lines. Our results indicate small-molecule DUB inhibitors have a profound effect on TNBC viability and lead to activation of autophagy as a cellular mechanism to compensate for ubiquitin-proteasome-system stress. Treatment with sub-optimal doses of DUB and lysosome inhibitors synergistically kills TNBC cells. This supports the evaluation of DUB inhibition, in combination with lysosomal inhibition, as a therapeutic approach for the treatment of TNBC.
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Rachel Isaksson
authors.initials: RI
authors.lastname: Vogel
authors.affiliation: Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Coughlin
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scotti
authors.affiliation: Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Iizuka
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Anchoori
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.|Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Richard B S
authors.initials: RB
authors.lastname: Roden
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Marastoni
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Bazzaro
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D061986:MCF-7 Cells; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D000077337:Vorinostat; D002738:Chloroquine; D064570:Ubiquitin-Specific Proteases; D046988:Proteasome Endopeptidase Complex