title: 6-Shogaol induces apoptosis in human hepatocellular carcinoma cells and exhibits anti-tumor activity in vivo through endoplasmic reticulum stress.
abstract: 6-Shogaol is an active compound isolated from Ginger (Zingiber officinale Rosc). In this work, we demonstrated that 6-shogaol induces apoptosis in human hepatocellular carcinoma cells in relation to caspase activation and endoplasmic reticulum (ER) stress signaling. Proteomic analysis revealed that ER stress was accompanied by 6-shogaol-induced apoptosis in hepatocellular carcinoma cells. 6-shogaol affected the ER stress signaling by regulating unfolded protein response (UPR) sensor PERK and its downstream target eIF2α. However, the effect on the other two UPR sensors IRE1 and ATF6 was not obvious. In prolonged ER stress, 6-shogaol inhibited the phosphorylation of eIF2α and triggered apoptosis in SMMC-7721 cells. Salubrinal, an activator of the PERK/eIF2α pathway, strikingly enhanced the phosphorylation of eIF2α in SMMC-7721 cells with no toxicity. However, combined treatment with 6-shogaol and salubrinal resulted in significantly increase of apoptosis and dephosphorylation of eIF2α. Overexpression of eIF2α prevented 6-shogaol-mediated apoptosis in SMMC-7721 cells, whereas inhibition of eIF2α by small interfering RNA markedly enhanced 6-shogaol-mediated cell death. Furthermore, 6-shogaol-mediated inhibition of tumor growth of mouse SMMC-7721 xenograft was associated with induction of apoptosis, activation of caspase-3, and inactivation of eIF2α. Altogether our results indicate that the PERK/eIF2α pathway plays an important role in 6-shogaol-mediated ER stress and apoptosis in SMMC-7721 cells in vitro and in vivo.
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors: Rong
authors: R
authors: Hu
authors: Ping
authors: P
authors: Zhou
authors: Yong-Bo
authors: YB
authors: Peng
authors: Xiaojun
authors: X
authors: Xu
authors: Jiang
authors: J
authors: Ma
authors: Qun
authors: Q
authors: Liu
authors: Lei
authors: L
authors: Zhang
authors: Xiao-Dong
authors: XD
authors: Wen
authors: Lian-Wen
authors: LW
authors: Qi
authors: Ning
authors: N
authors: Gao
authors: Ping
authors: P
authors: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D002396:Catechols / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015180:Electrophoresis, Gel, Two-Dimensional; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002396:Catechols; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C496827:salubrinal; D051742:Transcription Factor CHOP; C040115:shogaol; D019892:eIF-2 Kinase; D013890:Thiourea