NDV-D90 inhibits 17β-estradiol-mediated resistance to apoptosis by differentially modulating classic and nonclassic estrogen receptors in breast cancer cells

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 alpha (ER alpha) 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 ER alpha or the GPER in BC cells exposed to 17 beta-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/ER alpha axis and enhancing GPER expression but also by modulating the expression of several apoptosis-related proteins through ER alpha-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 ER alpha 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.

Automated summary

NDV-D90 promotes apoptosis in breast cancer cells exposed to estrogen by differentially regulating the expression of ER alpha and GPER. It induces apoptosis through intrinsic and extrinsic signaling pathways in ER-positive cells and mainly via intrinsic signaling pathway in ER-negative cells.