title: Enhanced antitumor effect of shikonin by inhibiting Endoplasmic Reticulum Stress via JNK/c-Jun pathway in human glioblastoma stem cells.
abstract: Though previous study demonstrated that shikonin could exert its antitumor activity by inducing apoptosis and necrosis, the pro-survival mechanisms involved in its antitumor process are still little to know. In the present study, for the first time, we found a protective mechanism was simultaneously activated which caused the reduced sensitivity of glioblastoma stem cells (GSCs) to the cytotoxicity of shikonin. Reduced active caspase-9 expression and enhanced mitochondrial membrane potential (MMP) were intriguingly observed within 24 h treatment by shikonin in GSCs. Further investigation identified that Endoplasmic Reticulum Stress (ERS) was involved in its antitumor process, which compromised the cytotoxicity of shikonin toward GSCs. Inhibiting ERS by 4-phenylbutyric acid (4-PBA) markedly enhanced the cytotoxicity of shikonin in GSCs. The consistent result was simultaneously observed in the GSCs-xenografted mice. Furthermore, our results identified that JNK/c-Jun pathway was involved in the antitumor process of shikonin, providing a mechanism by which ERS reduced the cytotoxicity of shikonin toward GSCs. Altogether, the novel observation in the present study identified that inhibiting ERS would be an attractive new approach to enhance the therapeutic potency of shikonin toward GSCs.
authors: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
authors: Jing
authors: J
authors: Liu
authors: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, PR China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, PR China.
authors: Ping
authors: P
authors: Wang
authors: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, PR China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, PR China.
authors: Yi-Xue
authors: YX
authors: Xue
authors: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
authors: Zhen
authors: Z
authors: Li
authors: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
authors: Cheng-Bin
authors: CB
authors: Qu
authors: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, PR China. Electronic address: liuyunhui2014@yeah.net.
authors: Yun-Hui
authors: YH
authors: Liu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008819:Mice, Nude; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; D009285:Naphthoquinones; C016101:shikonin; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Endoplasmic Reticulum Stress; Glioblastoma stem cells; JNK/c-Jun pathway; Shikonin; Unfolded protein response