Shan Peng, Tang Bo, Xie Shanshan, Zhang Zengling, Fan Jiehou, Wei Zheng, Song Chun
Department of General Surgery, The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Thyroid Gland and Breast Surgery, The Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Hubei, China.
J Cell Biochem. 2021 Jan;122(1):3-15. doi: 10.1002/jcb.28118. Epub 2020 Sep 28.
Newcastle disease virus (NDV) is endowed with the oncolytic ability to kill tumor cells, while rarely causing side effects in normal cells. Both estrogen receptor α (ERα) and the G protein estrogen receptor (GPER) modulate multiple biological activities in response to estrogen, including apoptosis in breast cancer (BC) cells. Here, we investigated whether NDV-D90, a novel strain isolated from natural sources in China, promoted apoptosis by modulating the expression of ERα or the GPER in BC cells exposed to 17β-estradiol (E2). We found that NDV-D90 significantly killed the tumor cell lines MCF-7 and BT549 in a time- and dose-dependent manner. We also found that NDV-D90 exerted its effects on the two cell lines mainly by inducing apoptosis but not necrosis. NDV-D90 induced apoptosis via the intrinsic and extrinsic signaling pathways in MCF-7 cells (ER-positive cells) during E2 exposure not only by disrupting the E2/ERα axis and enhancing GPER expression but also by modulating the expression of several apoptosis-related proteins through ERα-and GPER-independent processes. NDV-D90 promoted apoptosis via the intrinsic signaling pathway in BT549 cells (ER-negative cells), possibly by impairing E2-mediated GPER expression. Furthermore, NDV-D90 exerted its antitumor effects in vivo by inducing apoptosis. Overall, these results demonstrated that NDV-D90 promotes apoptosis by differentially modulating the expression of ERα and the GPER in ER-positive and negative BC cells exposed to estrogen, respectively, and can be utilized as an effective approach to treating BC.
新城疫病毒（NDV）具有杀死肿瘤细胞的溶瘤能力，同时在正常细胞中很少引起副作用。雌激素受体α（ERα）和G蛋白雌激素受体（GPER）均能调节多种生物学活性以响应雌激素，包括乳腺癌（BC）细胞的凋亡。在此，我们研究了从中国天然来源分离的新型毒株NDV-D90是否通过调节暴露于17β-雌二醇（E2）的BC细胞中ERα或GPER的表达来促进凋亡。我们发现NDV-D90以时间和剂量依赖性方式显著杀死肿瘤细胞系MCF-7和BT549。我们还发现NDV-D90对这两种细胞系的作用主要是通过诱导凋亡而非坏死。在E2暴露期间，NDV-D90不仅通过破坏E2/ERα轴和增强GPER表达，还通过ERα和GPER非依赖性过程调节几种凋亡相关蛋白的表达，从而通过内在和外在信号通路诱导MCF-7细胞（ER阳性细胞）凋亡。NDV-D90可能通过损害E2介导的GPER表达，经由内在信号通路促进BT549细胞（ER阴性细胞）凋亡。此外，NDV-D90通过诱导凋亡在体内发挥抗肿瘤作用。总体而言，这些结果表明，NDV-D90分别通过差异调节暴露于雌激素的ER阳性和阴性BC细胞中ERα和GPER的表达来促进凋亡，可作为治疗BC的有效方法。
