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

• Published in: Oncogene Vol. 34; no. 20; pp. 2597 - 2608
• Main Authors: De Mei, C, Ercolani, L, Parodi, C, Veronesi, M, Vecchio, C Lo, Bottegoni, G, Torrente, E, Scarpelli, R, Marotta, R, Ruffili, R, Mattioli, M, Reggiani, A, Wade, M, Grimaldi, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-05-2015; Nature Publishing Group
• Subjects: 101/6; 14/28; 14/34; 14/35; 38; 38/89; 631/154/1435/2418; 631/337/572; 631/80/39; 82/1; 82/80; 82/83; 96/106; Antineoplastic Agents - pharmacology; Apoptosis; Autophagy - drug effects; Autophagy - genetics; Cancer; Care and treatment; Cell Biology; Cell receptors; Cytotoxins - pharmacology; Drug Screening Assays, Antitumor; Gene expression; Genetic aspects; Health aspects; HEK293 Cells; Hep G2 Cells; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics; Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism; Oncology; Original; original-article; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - genetics; Repressor Proteins - metabolism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.203

REV-ERBα and REV-ERBβ nuclear receptors regulate several physiological processes, including circadian rhythm and metabolism. A previous study reported the
REV-ERB
α 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.