title: The imidazoline compound RX871024 promotes insulinoma cell death independent of AMP-activated protein kinase inhibition.
abstract: We have previously shown that the insulinotropic imidazoline compound RX871024 induces death of insulinoma MIN6 cells, an effect involving stimulation of c-Jun N-terminal kinase (JNK) and caspase 3. It has also been reported that AMP-activated protein kinase (AMPK) activates JNK and induces β-cell death. Here we show that RX871024, but not another insulinotropic imidazoline compound (BL11282), suppressed AMPK activity in MIN6 cells. The inhibitory effect of RX871024 on AMPK was supported by the observation that the imidazoline induced lipid droplet formation in the cytoplasm of MIN6 cells. This reflects stimulation of anabolic pathways and inhibition of catabolic pathways in the cell that happen under conditions when AMPK is inhibited. Activation of AMPK by 5-aminoimidazole-4-carboxamide riboside (AICAR) elevated basal and cytokine-induced death in primary β-cells and in insulinoma MIN6 cells. RX871024 aggravated AICAR-induced insulinoma MIN6 cell death regardless of the presence of pro-inflammatory cytokines. The specific cytotoxic effect of imidazoline compound RX871024 on insulinoma cell death but not primary β-cell death is independent of its action on AMPK and may suggest the possibility of using this type of compound in the treatment of insulinomas.
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, L1, 17176, Stockholm, SE, Sweden.
authors.forename: Irina I
authors.initials: II
authors.lastname: Zaitseva
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, L1, 17176, Stockholm, SE, Sweden. Sergei.Zaitsev@ki.se.|Belozersky Institute of Physico-Chemical Biology and Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119992, Russia. Sergei.Zaitsev@ki.se.
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Zaitsev
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, L1, 17176, Stockholm, SE, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects; D007340:Insulinoma / Q000188:drug therapy* / Q000378:metabolism; D008820:Mice, Obese; D010766:Phosphorylation / Q000187:drug effects; D012263:Ribonucleosides / Q000494:pharmacology
chemical_list: C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D000970:Antineoplastic Agents; C423844:BL 11282; D007093:Imidazoles; D007211:Indoles; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D055372:AMP-Activated Protein Kinases
keywords: AMPK; IL-1β; INFγ; Imidazoline; Pancreatic β-cell; TNFα