title: Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression.
abstract: Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERα biomodulator that selectively blocks proliferation of drug-resistant ERα-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen-ERα-regulated gene expression, BHPI is effective because it elicits sustained ERα-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen-ERα: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERα(+) cancer cells, BHPI rapidly hyperactivates plasma membrane PLCγ, generating inositol 1,4,5-triphosphate (IP3), which opens EnR IP3R calcium channels, rapidly depleting EnR Ca(2+) stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2α (eIF2α), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca(2+) levels, but the open EnR IP3R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI's novel mode of action, high potency, and effectiveness in therapy-resistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.
authors.affiliation: Departments of Biochemistry, College of Medicine, and.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Andruska
authors.affiliation: Departments of Biochemistry.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Food Science and Human Nutrition, and.
authors.forename: Xujuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Departments of Biochemistry.
authors.forename: Chengjian
authors.initials: C
authors.lastname: Mao
authors.affiliation: College of Medicine, and Molecular and Integrative Physiology.
authors.forename: Mathew M
authors.initials: MM
authors.lastname: Cherian
authors.affiliation: College of Medicine, and Molecular and Integrative Physiology.
authors.forename: Lily
authors.initials: L
authors.lastname: Mahapatra
authors.affiliation: College of Medicine, and Food Science and Human Nutrition, and University of Illinois Cancer Center, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: William G
authors.initials: WG
authors.lastname: Helferich
authors.affiliation: Departments of Biochemistry, College of Medicine, and University of Illinois Cancer Center, University of Illinois at Urbana-Champaign, Urbana, IL 61801 djshapir@illinois.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D061986:MCF-7 Cells; D008819:Mice, Nude; D015394:Molecular Structure; D014176:Protein Biosynthesis / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000599673:3,3-bis(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-indol-2-one; D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007211:Indoles; D054852:Small Molecule Libraries
keywords: breast cancer; drug discovery; estrogen receptor; ovarian cancer; unfolded protein response
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