Department of General Surgery, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Department of Urology, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FASEB J. 2020 Apr;34(4):5877-5891. doi: 10.1096/fj.201903045RR. Epub 2020 Mar 5.
Hepatocellular carcinoma (HCC) is one of most common cancers worldwide, however, the treatment for advanced HCC remains unsatisfactory. We focused on the function of the androgen receptor (AR) in HCC and tried to find new treatment strategy based on antiandrogen enzalutamide (Enz). Here, we found that olaparib, a FDA-approved PARP inhibitor, could enhance the cytotoxicity in HCC cells with a lower BRCA1 expression, and suppressing the AR with either Enz or AR-shRNA could further increase the olaparib sensitivity to better suppress the HCC cell growth via a synergistic mechanism that may involve suppressing the expression of BRCA1 and other DNA damage response (DDR) genes. Mechanism studies revealed that Enz/AR signaling might transcriptionally regulate the miR-146a-5p expression via binding to the Androgen Response Elements on its 5' promoter region, which could then lead to suppress the homologous recombination-related BRCA1 expression via direct binding to the mRNA 3'UTR. Preclinical studies using an in vivo mouse model also demonstrated that combining Enz plus olaparib led to better suppression of the HCC progression. Together, these in vitro/in vivo data suggest that combining Enz and olaparib may help in the development of a novel therapy to better suppress the HCC progression.
肝细胞癌 (HCC) 是全球最常见的癌症之一，然而，晚期 HCC 的治疗仍然不尽如人意。我们专注于雄激素受体 (AR) 在 HCC 中的功能，并试图基于抗雄激素恩扎鲁胺 (Enz) 找到新的治疗策略。在这里，我们发现奥拉帕利，一种 FDA 批准的 PARP 抑制剂，可增强 BRCA1 表达较低的 HCC 细胞的细胞毒性，并用 Enz 或 AR-shRNA 抑制 AR 可进一步提高奥拉帕利的敏感性，通过协同机制更好地抑制 HCC 细胞生长，该机制可能涉及抑制 BRCA1 和其他 DNA 损伤反应 (DDR) 基因的表达。机制研究表明，Enz/AR 信号可能通过结合其 5'启动子区域上的雄激素反应元件来转录调节 miR-146a-5p 的表达，然后通过直接结合 mRNA 3'UTR 来抑制同源重组相关的 BRCA1 表达。使用体内小鼠模型的临床前研究也表明，联合使用 Enz 和奥拉帕利可更好地抑制 HCC 进展。总之，这些体外/体内数据表明，联合使用 Enz 和奥拉帕利可能有助于开发新的治疗方法，以更好地抑制 HCC 进展。
