title: Dual inhibition of REV-ERBβ and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cells.
abstract: REV-ERBα and REV-ERBβ nuclear receptors regulate several physiological processes, including circadian rhythm and metabolism. A previous study reported the REV-ERBα gene to be co-overexpressed with ERBB2 in breast cancer cell lines. Surprisingly, we found that several tumor types, including a number of breast cancer cell lines, predominantly express the REV-ERBβ variant. This pattern was independent of ERBB2 and ER status, and opposite to that of non-cancer mammary epithelial HMEC cells, in which REV-ERBα was the major variant. Consistent with this molecular profile, REV-ERB target genes in both circadian and metabolic pathways were derepressed upon silencing of REV-ERBβ, but not REV-ERBα. Strikingly, we found that REV-ERBβ is a determinant of sensitivity to chloroquine, a clinically relevant lysosomotropic agent that suppresses autophagy. The cytoprotective function of REV-ERBβ appears to operate downstream of autophagy blockade. Through compound screening, we identified ARN5187, a novel lysosomotropic REV-ERBβ ligand with a dual inhibitory activity toward REV-ERB-mediated transcriptional regulation and autophagy. Remarkably, although ARN5187 and chloroquine share similar lysosomotropic potency and have a similar effect on autophagy inhibition, ARN5187 is significantly more cytotoxic. Collectively, our results reveal that dual inhibition of REV-ERBβ and autophagy is an effective strategy for eliciting cytotoxicity in cancer cells. Furthermore, our discovery of a novel inhibitor compound of both REV-ERB and autophagy may provide a scaffold for the discovery of new multifunctional anticancer agents.
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: De Mei
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Ercolani
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Parodi
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Veronesi
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Lo Vecchio
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bottegoni
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Torrente
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Scarpelli
authors.affiliation: EM Laboratory, Department of Nanochemistry, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Marotta
authors.affiliation: EM Laboratory, Department of Nanochemistry, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Ruffili
authors.affiliation: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mattioli
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Reggiani
authors.affiliation: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Wade
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Grimaldi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D003603:Cytotoxins / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; C064353:NR1D1 protein, human; C090977:NR1D2 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins