title: Downregulation of 26S proteasome catalytic activity promotes epithelial-mesenchymal transition.
abstract: The epithelial-mesenchymal transition (EMT) endows carcinoma cells with phenotypic plasticity that can facilitate the formation of cancer stem cells (CSCs) and contribute to the metastatic cascade. While there is substantial support for the role of EMT in driving cancer cell dissemination, less is known about the intracellular molecular mechanisms that govern formation of CSCs via EMT. Here we show that β2 and β5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells. Moreover, selective proteasome inhibition enabled mammary epithelial cells to acquire certain morphologic and functional characteristics reminiscent of cancer stem cells, including CD44 expression, self-renewal, and tumor formation. Transcriptomic analyses suggested that proteasome-inhibited cells share gene expression signatures with cells that have undergone EMT, in part, through modulation of the TGF-β signaling pathway. These findings suggest that selective downregulation of proteasome activity in mammary epithelial cells can initiate the EMT program and acquisition of a cancer stem cell-like phenotype. As proteasome inhibitors become increasingly used in cancer treatment, our findings highlight a potential risk of these therapeutic strategies and suggest a possible mechanism by which carcinoma cells may escape from proteasome inhibitor-based therapy.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Asoka
authors.initials: A
authors.lastname: Banno
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Garcia
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: van Baarsel
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Metz
authors.affiliation: Center for Computational Biology and Bioinformatics, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Fisch
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Christella E
authors.initials: CE
authors.lastname: Widjaja
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Justine
authors.initials: J
authors.lastname: Lopez
authors.affiliation: Center for Computational Biology and Bioinformatics, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Chang
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Geurink
authors.affiliation: Division of Chemical Biology, Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Leiden, The Netherlands.
authors.forename: Bogdan I
authors.initials: BI
authors.lastname: Florea
authors.affiliation: Division of Chemical Biology, Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Leiden, The Netherlands.
authors.forename: Hermen S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Bui
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.|Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.|Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Chang
mesh_terms: D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002461:Cell Line, Transformed; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D053208:Kaplan-Meier Estimate; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: EMT; TGF-beta; cancer stem cells; proteasome