La Xiaoqin, Zhang Lichao, Li Zhuoyu, Yang Peng, Wang Yingying
Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China.
School of Life Science, Shanxi University, Taiyuan 030006, China.
Oncotarget. 2017 Mar 28;8(13):20909-20924. doi: 10.18632/oncotarget.14959.
Berberine, an isoquinoline alkaloid extracted from Coptidis Rhizoma, has been shown to induce cancer cell autophagic death. Glucose regulated protein 78 (GRP78) is associated with stress-induced autophagy. However, the related mechanisms between berberine-induced cancer cell autophagy and GRP78 remain to be elucidated. Here, we report that berberine can induce autophagic cancer cell death by elevating levels of GRP78. These results further demonstrated that berberine enhanced GRP78 by suppression of ubiquitination / proteasomal degradation of GRP78 and activation of ATF6. Moreover, fluorescence spectrum assay revealed that berberine could bind to GRP78 and form complexes. Finally, co-IP analysis showed that the ability of GRP78 to bind to VPS34 was increased with berberine treatment. Taken together, our results suggest that berberine induces autophagic cancer cell death via enhancing GRP78 levels and the ability of GRP78 to bind to VPS34.
小檗碱是从黄连根茎中提取的一种异喹啉生物碱，已被证明可诱导癌细胞自噬性死亡。葡萄糖调节蛋白78（GRP78）与应激诱导的自噬有关。然而，小檗碱诱导癌细胞自噬与GRP78之间的相关机制仍有待阐明。在此，我们报告小檗碱可通过提高GRP78水平诱导癌细胞自噬性死亡。这些结果进一步证明，小檗碱通过抑制GRP78的泛素化/蛋白酶体降解和激活ATF6来增强GRP78。此外，荧光光谱分析显示小檗碱可与GRP78结合并形成复合物。最后，免疫共沉淀分析表明，小檗碱处理后GRP78与VPS34结合的能力增强。综上所述，我们的结果表明，小檗碱通过提高GRP78水平以及GRP78与VPS34结合的能力来诱导癌细胞自噬性死亡。
