State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Cell Prolif. 2018 Dec;51(6):e12518. doi: 10.1111/cpr.12518. Epub 2018 Aug 28.
Autophagy and apoptosis are major types of eukaryotic programmed cell death, and regulating these processes holds promise for treating cancers. In this study, we explored the regulation mechanisms of narciclasine to autophagy and apoptosis processes in triple-negative breast cancer.
Effects of narciclasine on proliferation, apoptosis, and autophagy of HCC-1937 and MDA-MB-231 triple-negative breast cancer (TNBC) cells were assessed using transmission electronic microscopy, flow cytometry following staining with Annexin V-FITC and propidium iodide, RNA sequencing, real-time PCR, and Western blotting. The ability of narciclasine to inhibit growth of human HCC1937 TNBC xenografts in mice was assessed, and potential mechanisms of inhibition were explored using immunohistochemistry.
Narciclasine inhibited TNBC cell proliferation and induced autophagy-dependent apoptosis in a dose-dependent manner. These apoptotic effects could be reversed using autophagy inhibitors, including an AMPK inhibitor and ULK1 siRNA. Consistent with these in vitro results, narciclasine significantly inhibited TNBC tumour growth in mice by upregulating autophagy-dependent apoptosis.
Our findings suggest that narciclasine regulates the AMPK-ULK1 signalling axis to promote autophagy-dependent apoptosis, demonstrating therapeutic potential against TNBC.
自噬和细胞凋亡是真核细胞程序性死亡的主要类型，调节这些过程有望治疗癌症。本研究探索了水仙尼定对三阴性乳腺癌中自噬和细胞凋亡过程的调控机制。
采用透射电镜、流式细胞术（Annexin V-FITC/PI 染色）、RNA 测序、实时 PCR 和 Western blot 等方法检测水仙尼定对 HCC-1937 和 MDA-MB-231 三阴性乳腺癌（TNBC）细胞增殖、凋亡和自噬的影响。通过免疫组织化学法探讨水仙尼定抑制人 HCC1937 TNBC 异种移植瘤生长的潜在机制。
水仙尼定呈剂量依赖性抑制 TNBC 细胞增殖，并诱导自噬依赖性细胞凋亡。这些凋亡作用可通过自噬抑制剂（包括 AMPK 抑制剂和 ULK1 siRNA）逆转。与这些体外结果一致，水仙尼定通过上调自噬依赖性凋亡显著抑制小鼠 TNBC 肿瘤生长。
本研究结果表明，水仙尼定通过调节 AMPK-ULK1 信号通路促进自噬依赖性细胞凋亡，为治疗 TNBC 提供了潜在的治疗作用。
