title: GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis.
abstract: Glycogen Synthase Kinase-3 alpha (GSK3A) and beta (GSK3B) isoforms are encoded by distinct genes, are 98% identical within their kinase domain and perform similar functions in several settings; however, they are not completely redundant and, depending on the cell type and differentiative status, they also play unique roles. We recently identified a role for GSK3B in drug resistance by demonstrating that its inhibition enables necroptosis in response to chemotherapy in p53-null drug-resistant colon carcinoma cells. We report here that, similarly to GSK3B, also GSK3A silencing/inhibition does not affect cell proliferation or cell cycle but only abolishes growth after treatment with DNA-damaging chemotherapy. In particular, blocking GSK3A impairs DNA repair upon exposure to DNA-damaging drugs. As a consequence, p53-null cells overcome their inability to undergo apoptosis and mount a necroptotic response, characterized by absence of caspase activation and RIP1-independent, PARP-dependent AIF nuclear re-localization. We therefore conclude that GSK3A is redundant with GSK3B in regulating drug-resistance and chemotherapy-induced necroptosis and suggest that inhibition of only one isoform, or rather partial inhibition of overall cellular GSK3 activity, is enough to re-sensitize drug-resistant cells to chemotherapy.
authors.affiliation: Department of Surgery and Traslational Medicine, Medical School, University of Milano-Bicocca, via Cadore 48, Monza, Italy; BiOnSil srl, via Cadore 48, Monza, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Grassilli
authors.affiliation: Department of Surgery and Traslational Medicine, Medical School, University of Milano-Bicocca, via Cadore 48, Monza, Italy.
authors.forename: Leonarda
authors.initials: L
authors.lastname: Ianzano
authors.affiliation: Department of Surgery and Traslational Medicine, Medical School, University of Milano-Bicocca, via Cadore 48, Monza, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bonomo
authors.affiliation: Department of Surgery and Traslational Medicine, Medical School, University of Milano-Bicocca, via Cadore 48, Monza, Italy.
authors.forename: Carola
authors.initials: C
authors.lastname: Missaglia
authors.affiliation: Department of Surgery and Traslational Medicine, Medical School, University of Milano-Bicocca, via Cadore 48, Monza, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cerrito
authors.affiliation: Department of Surgery and Traslational Medicine, Medical School, University of Milano-Bicocca, via Cadore 48, Monza, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giovannoni
authors.affiliation: Department of Surgery and Traslational Medicine, Medical School, University of Milano-Bicocca, via Cadore 48, Monza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Masiero
authors.affiliation: Department of Surgery and Traslational Medicine, Medical School, University of Milano-Bicocca, via Cadore 48, Monza, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Lavitrano
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009336:Necrosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D007527:Isoenzymes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha