The role and the molecular mechanism of abietic acid in the proliferation, invasion and migration of cisplatin-resistant nasopharyngeal carcinoma cells
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摘要: 目的 探讨枞酸在顺铂耐药鼻咽癌细胞增殖、侵袭、迁移的作用及分子机制。方法 ① 药物浓度递增法构建顺铂耐药鼻咽癌C666/DDP细胞株。②枞酸对C666/DDP细胞增殖、侵袭及迁移的影响研究：CCK-8法、活性氧(ROS)及线粒体膜电位(MMP)水平检测及裸鼠皮下成瘤实验检测枞酸对C666/DDP细胞体外、体内增殖及凋亡能力的影响；Transwell法检测细胞侵袭和迁移能力。③Western blot及IHC法检测PI3K/AKT/mTOR通路相关蛋白的表达情况。结果 ① 顺铂对C666-1细胞毒性IC50约为25 μmol/L。RI=25 μmol/L/4 μmol/L=6.25，获得耐药性，C666-1-DDP耐药株构建成功。②枞酸可促进C666/DDP细胞凋亡，抑制其增殖，且表现为G2/M期阻滞；Transwell显示枞酸抑制C666/DDP细胞迁移及侵袭能力，提高C666/DDP细胞ROS水平并使MMP降低。③动物实验显示枞酸在体内呈浓度梯度抑制顺铂耐药鼻咽癌的增殖，抑制PI3K/AKT/mTOR信号通路相关蛋白的表达。结论 枞酸可抑制顺铂耐药鼻咽癌细胞增殖、侵袭及迁移，其机制与抑制PI3K/AKT/mTOR信号通路有关。Abstract: Objective To investigate the effects and molecular mechanisms of abietic acid in the cell proliferation, invasion and migration of cisplatin-resistant nasopharyngeal carcinoma cells.Methods ① Cisplatin-resistant C666/DDP cell line was constructed by increasing drug concentration method. ②The effects of abietic acid on proliferation, invasion and migration of C666/DDP cells were investigated by CCK-8 method, reactive oxygen species(ROS) and mitochondrial membrane potential(MMP) level assay and subcutaneous tumorigenesis assay in nude mice to detect the effects of abietic acid on proliferation and apoptosis of C666/DDP cells in vitro and in vivo. The effect of abietic acid on the proliferation and apoptosis of C666/DDP cells in vitro and in vivo was measured by Transwell assay. ③Western blot and IHC method to detect the expression of PI3K/AKT/mTOR pathway related proteins.Results ① The IC50 of cisplatin cytotoxicity to C666-1 was about 25 μmol/L. RI=25 μmol/L /4 μmol/L=6.25, resistance was obtained, and the C666-1-DDP resistant strain was successfully constructed. ②Abietic acid promoted apoptosis and inhibited proliferation of C666/DDP cells, and showed G2/M phase block; transwell showed that abietic acid inhibited C666/DDP cell migration and invasion, increased ROS level of C666/DDP cells and decreased MMP. Transwell showed that abietic acid inhibited the migration and invasion ability of C666/DDP cells, increased the ROS level of C666/DDP cells and decreased MMP. ③Animal experiments showed that abietic acid inhibited the proliferation of cisplatin-resistant nasopharyngeal carcinoma in vivo in a concentration gradient and suppressed the expression of PI3K/AKT/mTOR signaling pathway-related proteins.Conclusion Abietic acid inhibits proliferation, invasion and migration of cisplatin-resistant nasopharyngeal carcinoma cells by a mechanism related to inhibition of PI3K/AKT/mTOR signaling pathway.
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Key words:
- abietic acid /
- nasopharyngeal carcinoma /
- cisplatin resistance /
- molecular mechanism
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