title: A novel derivative of tetrandrine (H1) induces endoplasmic reticulum stress-mediated apoptosis and prosurvival autophagy in human non-small cell lung cancer cells.
abstract: H1, a bromized derivative of tetrandrine, has been reported to induce apoptosis in human cancer cells. But, the underlying mechanism of apoptosis triggered by H1 is unclear. In the present study, we found that H1 triggered death receptor 5 (DR5)-dependent apoptosis in non-small cell lung cancer (NSCLC) cells. Further study showed that H1 activated ER stress through enforcing the expression of Bip/GRP78, IRE1α, p-eIF2α, and CHOP. Moreover, abrogating CHOP expression blocked DR5 upregulation and subsequent apoptosis, indicating that CHOP was essential for DR5-dependent apoptosis induced by H1. In addition, H1 greatly downregulated cellular FLICE-inhibitory protein (c-FLIP), and enhanced expression of c-FLIP protected cancer cells from apoptosis in spite of H1 therapy. Furthermore, we discovered that H1 induced autophagy in human NSCLC cells. Interestingly, the autophagy induced by H1 played a protective function in NSCLC cells and effectively weakened caspase-mediated apoptosis. In summary, these findings suggest that H1 induces DR5-dependent apoptosis in human NSCLC cells via stimulating ER stress signaling pathway, and pharmacologically inhibiting autophagy will be an efficient approach to synergize H1-caused apoptosis in lung cancer cells.
authors: The Thoracic Surgery Department of West China Hospital, West China Medical School of Sichuan University, Chengdu, China.
authors: Yidan
authors: Y
authors: Lin
authors: The Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Rm 103, South BLDG, 27 Shanda South Road, Jinan, 250100, China.
authors: Yu
authors: Y
authors: Wang
authors: The Department of Otolaryngology Head and Neck Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors: Xianfang
authors: X
authors: Liu
authors: The Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Rm 103, South BLDG, 27 Shanda South Road, Jinan, 250100, China.
authors: Jiamei
authors: J
authors: Yan
authors: The Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Rm 103, South BLDG, 27 Shanda South Road, Jinan, 250100, China.
authors: Ling
authors: L
authors: Su
authors: The Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Rm 103, South BLDG, 27 Shanda South Road, Jinan, 250100, China. xgliu@sdu.edu.cn.
authors: Xiangguo
authors: X
authors: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D044182:Benzylisoquinolines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C009438:tetrandrine
keywords: Apoptosis; Autophagy; CHOP; DR5; ER stress; Tetrandrine; c-FLIP