title: Endoplasmic reticulum stress activation mediates Ginseng Rg3-induced anti-gallbladder cancer cell activity.
abstract: In the current study, we examined the potential effect of Ginsenoside Rg3 against gallbladder cancer cells, the underlying signaling mechanisms were also studied. We demonstrated that Rg3 exerted potent cytotoxic and pro-apoptotic activity against established and primary human gallbladder cancer cells. Yet it was safe to non-cancerous gallbladder epithelial cells. At the molecular level, we showed that Rg3 induced endoplasmic reticulum (ER) stress activation, the latter was evidenced by C/EBP homologous protein (CHOP) upregulation, inositol-requiring enzyme 1 (IRE1)/PKR-like endoplasmic reticulum kinase (PERK) phosphorylations, and caspase-12 activation in gallbladder cancer cells. Reversely, the ER stress inhibitor salubrinal, the caspase-12 inhibitor z-ATAD-fmk as well as CHOP shRNA knockdown significantly attenuated Rg3-induced cytotoxicity against gallbladder cancer cells. In vivo, we showed that Rg3 oral administration significantly inhibited GBC-SD gallbladder cancer xenograft growth in nude mice, its activity was, however, compromised with co-administration of the ER stress inhibitor salubrinal. Thus, we suggest that ER stress activation mediates Ginseng Rg3-induced anti-gallbladder cancer cell activity in vitro and in vivo.
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Keren
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Huaqin
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Fa
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Minimally Invasive, Hospital of Integrated Chinese and Western Medicine in Zhejiang Province, Hangzhou, China. Electronic address: Jifengnie163@163.com.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Nie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis; D053454:Caspase 12 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured / Q000166:cytology; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000378:metabolism; D005706:Gallbladder Neoplasms / Q000378:metabolism*; D020869:Gene Expression Profiling; D036145:Ginsenosides / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D005894:Panax / Q000737:chemistry*; D051742:Transcription Factor CHOP / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D036145:Ginsenosides; D051742:Transcription Factor CHOP; C097367:ginsenoside Rg3; D053454:Caspase 12
keywords: CHOP; Endoplasmic reticulum stress; Gallbladder cancer; Ginseng Rg3; Nude mice