Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Rytime Dental, Chongqing, China.
Cancer Lett. 2019 Apr 28;448:94-104. doi: 10.1016/j.canlet.2019.02.004. Epub 2019 Feb 8.
Activated Akt and ERK signaling pathways are closely related to breast cancer progression, and Akt or ERK inhibition induces cell senescence. However, the crosstalk between the Akt and ERK signaling pathways in cell senescence and how to simultaneously suppress Akt and ERK signaling in triple-negative breast cancer (TNBC) are undefined. In this study, we found that norcantharidin (NCTD) effectively induced cell senescence and cell cycle arrest in TNBC in vitro, which was accompanied by a decline in phosphorylated Akt and ERK1/2 and a rise in p21 and p16. The inhibitors LY294002 and U0126 imitated the effect of NCTD when these two inhibitors were combined regardless of crosstalk between these two signaling pathways. In addition, NCTD inhibited the growth of xenografts via downregulation of phosphorylated Akt and ERK1/2 and upregulation of p21 in vivo. However, NCTD upregulated the level of soluble signaling factors of the senescence-associated secretory phenotype (SASP) in a NF-κB-independent manner. Collectively, these findings demonstrate that NCTD induced cell senescence and cell cycle arrest mainly by simultaneously blocking Akt and ERK signaling in TNBC, suggesting that NCTD may be used as a potential adjuvant therapy in TNBC.
激活的 Akt 和 ERK 信号通路与乳腺癌的进展密切相关，Akt 或 ERK 的抑制诱导细胞衰老。然而，Akt 和 ERK 信号通路在细胞衰老中的相互作用以及如何同时抑制三阴性乳腺癌 (TNBC) 中的 Akt 和 ERK 信号通路尚不清楚。在本研究中，我们发现去甲斑蝥素 (NCTD) 可有效诱导体外 TNBC 细胞衰老和细胞周期停滞，同时伴随着磷酸化 Akt 和 ERK1/2 的下降以及 p21 和 p16 的上升。LY294002 和 U0126 抑制剂无论这两种信号通路是否存在串扰，联合使用时均可模拟 NCTD 的作用。此外，NCTD 通过下调体内磷酸化 Akt 和 ERK1/2 以及上调 p21 来抑制异种移植物的生长。然而，NCTD 以 NF-κB 非依赖性方式上调衰老相关分泌表型 (SASP) 的可溶性信号因子水平。综上所述，这些发现表明 NCTD 通过同时阻断 TNBC 中的 Akt 和 ERK 信号通路诱导细胞衰老和细胞周期停滞，提示 NCTD 可能可作为 TNBC 的一种潜在辅助治疗方法。
