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Dual inhibition of REV-ERB? and autophagy as a novel pharmacological approach to
induce cytotoxicity in cancer cells
#MMPMID25023698
De Mei C
; Ercolani L
; Parodi C
; Veronesi M
; Lo Vecchio C
; Bottegoni G
; Torrente E
; Scarpelli R
; Marotta R
; Ruffili R
; Mattioli M
; Reggiani A
; Wade M
; Grimaldi B
Oncogene
2015[May]; 34
(20
): 2597-608
PMID25023698
show ga
REV-ERB? and REV-ERB? nuclear receptors regulate several physiological processes,
including circadian rhythm and metabolism. A previous study reported the REV-ERB?
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-ERB? variant. This pattern was independent
of ERBB2 and ER status, and opposite to that of non-cancer mammary epithelial
HMEC cells, in which REV-ERB? 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-ERB?, but not REV-ERB?. Strikingly, we
found that REV-ERB? is a determinant of sensitivity to chloroquine, a clinically
relevant lysosomotropic agent that suppresses autophagy. The cytoprotective
function of REV-ERB? appears to operate downstream of autophagy blockade. Through
compound screening, we identified ARN5187, a novel lysosomotropic REV-ERB? 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-ERB? 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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