Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, People's Republic of China.
Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.
Theranostics. 2020 Mar 15;10(10):4466-4480. doi: 10.7150/thno.42478. eCollection 2020.
: The circadian clock coordinates cell proliferation and metabolism and impacts the progression of some diseases, particularly cancer. Pharmacological modulation of the circadian machinery may be an effective therapeutic approach for treating cancer. SR9009 is a specific synthetic agonist of the REV-ERBs, essential circadian clock components. However, the potential efficacy and antitumor mechanism of this drug in small-cell lung cancer (SCLC) remains poorly understood. : Here, we used chemosensitive cells (H69 and H446) and the corresponding chemoresistant cells (H69AR and H446DDP) to assess the efficacy of the REV-ERB agonist SR9009 for the treatment of SCLC and further validated the antitumor effect in subcutaneous tumor models of SCLC. Then, we determined whether REV-ERBα was correlated with the anti-SCLC effect of SR9009. Chromatin immunoprecipitation (ChIP) sequencing assays were conducted to identify potential DNA sequences directly regulated by REV-ERBα. Autophagy regulation by REV-ERBα and its possible mechanism in SR9009-based SCLC therapy were analyzed. : Here, we showed that the REV-ERB agonist SR9009 is specifically lethal to both chemosensitive and chemoresistant SCLC cells. REV-ERBα was involved in the antitumor effect of SR9009 in SCLC. The core autophagy gene Atg5 was identified as a direct downstream target of REV-ERBα and was suppressed by the REV-ERB agonist SR9009 in SCLC. Furthermore, the interaction of REV-ERBα with this autophagy gene impaired autophagy activity, leading to SR9009 cytotoxicity in SCLC cells. : Our study provided a novel viewpoint indicating that the REV-ERB agonist SR9009 could be a novel and promising therapeutic strategy in first- or second-line SCLC treatment. The anti-SCLC effect of SR9009 is mediated by REV-ERB dependent suppression of autophagy via direct repression of the autophagy gene Atg5.
: 昼夜节律钟协调细胞增殖和代谢，并影响某些疾病（尤其是癌症）的进展。调节昼夜节律钟机制可能是治疗癌症的一种有效治疗方法。SR9009 是 REV-ERBs 的一种特异性合成激动剂，REV-ERBs 是昼夜节律钟的重要组成部分。然而，这种药物在小细胞肺癌 (SCLC) 中的潜在疗效和抗肿瘤机制仍知之甚少。 : 在这里，我们使用化学敏感性细胞（H69 和 H446）和相应的化学抗性细胞（H69AR 和 H446DDP）来评估 REV-ERB 激动剂 SR9009 治疗 SCLC 的疗效，并进一步验证了 SCLC 皮下肿瘤模型中的抗肿瘤作用。然后，我们确定了 REV-ERBα 是否与 SR9009 的抗 SCLC 作用相关。进行染色质免疫沉淀 (ChIP) 测序实验以鉴定直接受 REV-ERBα 调控的潜在 DNA 序列。分析了 REV-ERBα 对自噬的调节及其在基于 SR9009 的 SCLC 治疗中的可能机制。 : 在这里，我们表明 REV-ERB 激动剂 SR9009 对化学敏感性和化学抗性 SCLC 细胞均具有特异性杀伤作用。REV-ERBα 参与了 SR9009 在 SCLC 中的抗肿瘤作用。核心自噬基因 Atg5 被鉴定为 REV-ERBα 的直接下游靶标，并被 REV-ERB 激动剂 SR9009 在 SCLC 中抑制。此外，REV-ERBα 与该自噬基因的相互作用会削弱自噬活性，导致 SCLC 细胞中 SR9009 的细胞毒性。 : 我们的研究提供了一个新的观点，表明 REV-ERB 激动剂 SR9009 可能成为 SCLC 一线或二线治疗的一种新的有前途的治疗策略。SR9009 的抗 SCLC 作用是通过直接抑制自噬基因 Atg5 来调节 REV-ERB 依赖性自噬抑制来介导的。
