title: Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors.
abstract: The synthetic steroid mifepristone blocks the growth of ovarian cancer cells, yet the mechanism driving such effect is not entirely understood. Unbiased genomic and proteomic screenings using ovarian cancer cell lines of different genetic backgrounds and sensitivities to platinum led to the identification of two key genes upregulated by mifepristone and involved in the unfolded protein response (UPR): the master chaperone of the endoplasmic reticulum (ER), glucose regulated protein (GRP) of 78 kDa, and the CCAAT/enhancer binding protein homologous transcription factor (CHOP). GRP78 and CHOP were upregulated by mifepristone in ovarian cancer cells regardless of p53 status and platinum sensitivity. Further studies revealed that the three UPR-associated pathways, PERK, IRE1α, and ATF6, were activated by mifepristone. Also, the synthetic steroid acutely increased mRNA translation rate, which, if prevented, abrogated the splicing of XBP1 mRNA, a non-translatable readout of IRE1α activation. Moreover, mifepristone increased LC3-II levels due to increased autophagic flux. When the autophagic-lysosomal pathway was inhibited with chloroquine, mifepristone was lethal to the cells. Lastly, doses of proteasome inhibitors that are inadequate to block the activity of the proteasomes, caused cell death when combined with mifepristone; this phenotype was accompanied by accumulation of poly-ubiquitinated proteins denoting proteasome inhibition. The stimulation by mifepristone of ER stress and autophagic flux offers a therapeutic opportunity for utilizing this compound to sensitize ovarian cancer cells to proteasome or lysosome inhibitors.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Hapon
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA; Department of Pathology, Faculty of Medicine, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Goyeneche
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Srinivasan
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Gamarra-Luques
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Callegari
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Donis D
authors.initials: DD
authors.lastname: Drappeau
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Terpstra
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Pan
authors.affiliation: Kansas Intellectual and Development Disabilities Research Center, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Knapp
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Eyster
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA; Department of Pathology, Faculty of Medicine, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address: carlos.telleria@mcgill.ca.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Telleria
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D015735:Mifepristone / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D010984:Platinum / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D011691:Puromycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: C497109:ATF4 protein, human; D002934:Cinnamates; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; C496827:salubrinal; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D015735:Mifepristone; D010984:Platinum; D011691:Puromycin; D002738:Chloroquine; D013890:Thiourea
keywords: Autophagic flux; Bortezomib; Chloroquine; ER stress; Mifepristone; Ovarian cancer; Ubiquitin proteasome system; Unfolded protein response; mRNA translation