Kong Lu, Liu Xu, Yu Bing, Yuan Ye, Zhao Qianru, Chen Yuru, Qu Bin, Du Xue, Tian Xiaoxuan, Shao Rui, Wang Yu
School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Laboratory of Pharmacology of TCM Formulae Co-Constructed by the Province-Ministry, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Front Pharmacol. 2022 Apr 5;13:797873. doi: 10.3389/fphar.2022.797873. eCollection 2022.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC), which is characterized by the total absence of human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), and estrogen receptor (ER) expression. Cinobufacini injection (CI) is the aqueous extract from the dry skin of , which is broadly used for the treatment of malignant tumors. However, the potential mechanism of CI against TNBC has not been fully revealed. In this study, we found that CI inhibited the proliferation of MDA-MB-231 and 4T1 cells in a time- and dose-dependent manner. RNA-seq data showed that downregulated and upregulated genes were mainly enriched in biological processes related to tumor cell proliferation, including cell cycle arrest and regulation of apoptosis signaling pathways. Indeed, after CI treatment, the protein level of CDK1 and Bcl-2/Bax decreased, indicating that CI induced the cell cycle of MDA-MB-231 arrest in the G2/M phase and increased the rate of apoptosis. Meanwhile, CI significantly inhibited the growth of tumor , and RNA-seq data showed that the TAZ signaling pathway played a vital role after CI treatment. Both immunohistochemistry and Western blot analysis confirmed the downregulation of Pin1 and TAZ, caused by CI treatment. Furthermore, the bioinformatics analysis indicated that Pin1 and TAZ were indeed elevated in TNBC patients, with poor staging, classification, and patient survival rate. In conclusion, CI effectively inhibited the proliferation of TNBC and and induced their apoptosis and cycle arrest through the Pin1-TAZ pathway.
三阴性乳腺癌（TNBC）是乳腺癌（BC）的一种侵袭性亚型，其特征是完全不存在人表皮生长因子受体2（HER2）、孕激素受体（PR）和雌激素受体（ER）表达。华蟾素注射液（CI）是从中华大蟾蜍干皮中提取的水性提取物，广泛用于治疗恶性肿瘤。然而，CI抗TNBC的潜在机制尚未完全揭示。在本研究中，我们发现CI以时间和剂量依赖性方式抑制MDA-MB-231和4T1细胞的增殖。RNA测序数据显示，下调和上调的基因主要富集在与肿瘤细胞增殖相关的生物学过程中，包括细胞周期停滞和凋亡信号通路的调节。事实上，CI处理后，CDK1和Bcl-2/Bax的蛋白水平降低，表明CI诱导MDA-MB-231细胞周期停滞在G2/M期并增加凋亡率。同时，CI显著抑制肿瘤生长，RNA测序数据显示TAZ信号通路在CI处理后起重要作用。免疫组织化学和蛋白质印迹分析均证实CI处理导致Pin1和TAZ下调。此外，生物信息学分析表明，Pin1和TAZ在TNBC患者中确实升高，分期、分级较差，患者生存率较低。总之，CI通过Pin1-TAZ途径有效抑制TNBC细胞的增殖并诱导其凋亡和周期停滞。
