Dual inhibition of REV-ERBβ and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cells.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE

Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-

Antineoplastic Agents/*pharmacology ; Autophagy/*drug effects ; Cytotoxins/*pharmacology ; Neoplasms/*drug therapy ; Receptors, Cytoplasmic and Nuclear/*antagonists & inhibitors ; Repressor Proteins/*antagonists & inhibitors; Autophagy/genetics ; Drug Screening Assays, Antitumor ; HEK293 Cells ; Hep G2 Cells ; Humans ; Neoplasms/genetics ; Neoplasms/metabolism ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; Nuclear Receptor Subfamily 1, Group D, Member 1/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism

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.

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0 (Antineoplastic Agents)
0 (Cytotoxins)
0 (NR1D1 protein, human)
0 (NR1D2 protein, human)
0 (Nuclear Receptor Subfamily 1, Group D, Member 1)
0 (Receptors, Cytoplasmic and Nuclear)
0 (Repressor Proteins)

Date Created: 20140716 Date Completed: 20150729 Latest Revision: 20230815

20231215

PMC4761647

10.1038/onc.2014.203

25023698