title: AICAR activates ER stress-dependent apoptosis in gallbladder cancer cells.
abstract: AICAR (5-Aminoimidazole-4-carboxamide riboside or acadesine) is an AMP-activated protein kinase (AMPK) agonist, its activity in human gallbladder cancer cells was evaluated here. We show that AICAR provoked significant apoptosis in human gallbladder cancer cell lines (Mz-ChA-1, QBC939 and GBC-SD) and primary gallbladder cancer cells. AICAR-induced cytotoxicity in gallbladder cancer cells appears independent of AMPK activation. Inhibition of AMPK, via AMPKα shRNA knockdown or dominant negative mutation (T172A), failed to rescue GBC-SD cells from AICAR. Further, forced-activation of AMPK, by adding two other AMPK activators (A769662 and Compound 13), or expressing a constitutively-active mutant AMPKα (T172D), didn't induce GBC-SD cell death. Remarkably, AICAR treatment in gallbladder cancer cells induced endoplasmic reticulum (ER) stress activation, the latter was tested by caspase-12 activation, C/EBP homologous protein (CHOP) expression and IRE1/PERK phosphorylation. Contrarily, salubrinal (the ER stress inhibitor), z-ATAD-fmk (the caspase-12 inhibitor) or CHOP shRNAs significantly attenuated AICAR-induced gallbladder cancer cell apoptosis. Together, we conclude that AICAR-induced gallbladder cancer cell apoptosis requires ER stress activation, but is independent of AMPK.
authors.affiliation: Department of Minimally Invasive Surgery, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Nie
authors.affiliation: Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, China.
authors.forename: Aidong
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Minimally Invasive Surgery, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, China.
authors.forename: Qunya
authors.initials: Q
authors.lastname: Tan
authors.affiliation: Department of Minimally Invasive Surgery, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Minimally Invasive Surgery, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Hu
authors.affiliation: Department of Minimally Invasive Surgery, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Minimally Invasive Surgery, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yan
authors.affiliation: Department of Minimally Invasive Surgery, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, China. Electronic address: zhoulizjph@163.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D012265:Ribonucleotides / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: AICAR; AMPK; Apoptosis and gallbladder cancer cells; ER stress