GSK3A Is Redundant with GSK3B in Modulating Drug Resistance and Chemotherapy-Induced Necroptosis

• Published in: PloS one Vol. 9; no. 7; p. e100947
• Main Authors: Grassilli, Emanuela, Ianzano, Leonarda, Bonomo, Sara, Missaglia, Carola, Cerrito, Maria Grazia, Giovannoni, Roberto, Masiero, Laura, Lavitrano, Marialuisa
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2014; Public Library of Science (PLoS)
• Subjects: Alzheimer's disease; Alzheimers disease; Apoptosis; Apoptosis-inducing factor; Autophagy; Biology and Life Sciences; Brain cancer; Cancer therapies; Caspase; Cell cycle; Cell death; Cell Line, Tumor; Cell proliferation; Chemotherapy; Coding; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - enzymology; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Drug resistance; Drug Resistance, Neoplasm; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Glycogen synthesis; Humans; Inhibition; Isoenzymes - genetics; Isoenzymes - metabolism; Isoforms; Kinases; Localization; Medical schools; Medicine; Medicine and Health Sciences; Melanoma; Necroptosis; Necrosis; Null cells; p53 Protein; Pancreatic cancer; Phosphorylation; Poly(ADP-ribose) polymerase; Proteins; Redundancy; Rodents; Surgery; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0100947

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.