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

• DOI: 10.1038/onc.2014.203
• Publication Date: 2014-07-16T07:05:19Z
• Authors: C De Mei; L Ercolani; C Parodi; M Veronesi; C Lo Vecchio; G Bottegoni; E Torrente; R Scarpelli; R Marotta; R Ruffili; M Mattioli; A Reggiani; M Wade; B Grimaldi
• Keywords: 0303 health sciences; Cytotoxins; Receptors, Cytoplasmic and Nuclear; Antineoplastic Agents; Hep G2 Cells; 3. Good health; Repressor Proteins; 03 medical and health sciences; HEK293 Cells; Neoplasms; Nuclear Receptor Subfamily 1, Group D, Member 1; Autophagy; Humans; Original Article; Drug Screening Assays, Antitumor

REV-ERBα and REV-ERBβ nuclear receptors regulate several physiological processes, including circadian rhythm metabolism. A previous study reported the gene to be co-overexpressed with ERBB2 in breast cancer cell lines. Surprisingly, we found that tumor types, a number of lines, predominantly express variant. This pattern was independent ER status, opposite non-cancer mammary epithelial HMEC cells, which major Consistent this molecular profile, REV-ERB target genes both metabolic pathways were derepressed upon silencing REV-ERBβ, but not REV-ERBα. Strikingly, is determinant sensitivity chloroquine, clinically relevant lysosomotropic agent suppresses autophagy. The cytoprotective function appears operate downstream autophagy blockade. Through compound screening, identified ARN5187, novel ligand dual inhibitory activity toward REV-ERB-mediated transcriptional regulation Remarkably, although ARN5187 chloroquine share similar potency have effect on inhibition, significantly more cytotoxic. Collectively, our results reveal inhibition an effective strategy for eliciting cytotoxicity cells. Furthermore, discovery inhibitor may provide scaffold new multifunctional anticancer agents.