Central Laboratory, Navy General Hospital, Beijing 100048, P.R. China.
Int J Mol Med. 2019 Apr;43(4):1866-1878. doi: 10.3892/ijmm.2019.4089. Epub 2019 Feb 1.
Beclin1, a key regulator of autophagy, has been demonstrated to be associated with cancer cell resistance to chemotherapy. Paclitaxel is a conventional chemotherapeutic drug used in the clinical treatment of breast cancer. However, the function and mechanism of Beclin1 in paclitaxel‑mediated cytotoxicity in breast cancer are not well defined. The present study demonstrated that paclitaxel suppressed cell viability and Beclin1 expression levels in BT‑474 breast cancer cells in a dose‑ and time‑dependent fashion. Compared with the control, the knockdown of Beclin1 significantly enhanced breast cancer cell death via the induction of caspase‑dependent apoptosis following paclitaxel treatment in vitro (P<0.05). In a BT‑474 xenograft model, paclitaxel achieved substantial inhibition of tumor growth in the Beclin1 knockdown group compared with the control group. Furthermore, analysis of the publicly available Gene Expression Omnibus datasets revealed a clinical correlation between Beclin1 levels and the response to paclitaxel therapy in patients with breast cancer. Collectively, the present results suggest that Beclin1 protects breast cancer cells from apoptotic death. Thus, the inhibition of Beclin1 may be a novel way to improve the effect of paclitaxel. Additionally, Beclin1 may function as a favorable prognostic biomarker for paclitaxel treatment in patients with breast cancer.
自噬关键调节因子 Beclin1 已被证实与癌细胞对化疗的耐药性有关。紫杉醇是一种常规的化疗药物，用于乳腺癌的临床治疗。然而，Beclin1 在紫杉醇介导的乳腺癌细胞毒性中的功能和机制尚未明确。本研究表明，紫杉醇呈剂量和时间依赖性方式抑制 BT-474 乳腺癌细胞的活力和 Beclin1 表达水平。与对照组相比，Beclin1 敲低显著增强了乳腺癌细胞的死亡，这是通过紫杉醇处理后诱导 caspase 依赖性细胞凋亡实现的（P<0.05）。在 BT-474 异种移植模型中，与对照组相比，Beclin1 敲低组紫杉醇实现了对肿瘤生长的实质性抑制。此外，对公开的基因表达综合数据库数据集的分析显示，Beclin1 水平与乳腺癌患者对紫杉醇治疗的反应之间存在临床相关性。综上所述，本研究结果表明 Beclin1 可保护乳腺癌细胞免受凋亡性死亡。因此，抑制 Beclin1 可能是提高紫杉醇疗效的一种新方法。此外，Beclin1 可能是乳腺癌患者紫杉醇治疗的有利预后生物标志物。
