Berberine-induced autophagic cell death by elevating GRP78 levels in cancer cells

// Xiaoqin La 1, * , Lichao Zhang 1, 2, * , Zhuoyu Li 1 , Peng Yang 1 , Yingying Wang 1 1 Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China 2 School of Life Science, Shanxi University, Taiyuan 030006, China * These authors have contributed equally to this work Correspondence to: Zhuoyu Li, email: lzy@sxu.edu.cn Keywords: berberine, autophagy, cancer cell death, GRP78, VPS34 Received: May 13, 2016     Accepted: January 10, 2017     Published: February 01, 2017 ABSTRACT 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.