Dual inhibition of REV-ERBβ and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cells.
Dual inhibition of REV-ERBβ and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cells.
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DOI：
10.1038/onc.2014.203
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发表时间：
2015-05-14
期刊：
影响因子：
8
通讯作者：
Grimaldi B
中科院分区：
文献类型：
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作者：
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
REV-ERBα和REV-ERBβ核受体调节多种生理过程，包括昼夜节律和代谢。先前的一项研究报告了REV-ERBα基因在乳腺癌细胞系中与ERBB 2共过表达。令人惊讶的是，我们发现几种肿瘤类型，包括一些乳腺癌细胞系，主要表达REV-ERBβ变体。这种模式与ERBB 2和ER状态无关，与非癌乳腺上皮HMEC细胞相反，其中REV-ERBα是主要变异体。与这种分子特征一致，昼夜节律和代谢途径中的REV-ERB靶基因在REV-ERBβ沉默后被去抑制，但REV-ERBα不受抑制。引人注目的是，我们发现REV-ERBβ是对氯喹敏感性的决定因素，氯喹是一种临床相关的抑制自噬的溶酶体药物。REV-ERBβ的细胞保护功能似乎在自噬阻断的下游起作用。通过化合物筛选，我们鉴定了ARN 5187，一种新的亲溶酶体REV-ERBβ配体，对REV-ERB介导的转录调控和自噬具有双重抑制活性。值得注意的是，尽管ARN 5187和氯喹具有相似的促溶酶体效力，并且对自噬抑制具有相似的作用，但ARN 5187的细胞毒性显著更强。总的来说，我们的结果表明，REV-ERBβ和自噬的双重抑制是在癌细胞中引发细胞毒性的有效策略。此外，我们发现了一种新的REV-ERB和自噬抑制剂化合物，这可能为发现新的多功能抗癌药物提供了一个支架。
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.