title: Nutritional limitation sensitizes mammalian cells to GSK-3β inhibitors and leads to growth impairment.
abstract: The serine/threonine kinase GSK-3β was initially described as a key enzyme involved in glucose metabolism, but it is now known to regulate a wide range of biological processes, including proliferation and apoptosis. We previously reported a transformation-dependent cell death induced by glucose limitation in K-ras-transformed NIH3T3. To address the mechanism of this phenomenon, we analyzed GSK-3β regulation in these cells in conditions of high versus low glucose availability. We found that glucose depletion caused a marked inhibition of GSK-3β through posttranslational mechanisms and that this inhibition was much less pronounced in normal cells. Further inhibition of GSK-3β with lithium chloride, combined with glucose shortage, caused specific activation of AMP-activated protein kinase and significant suppression of proliferation in transformed but not normal cells. The cooperative effect of lithium and low glucose availability on cell growth did not seem to depend exclusively on ras pathway activation because two human cell lines, A549 and MDA-MB-231, both harboring an activated ras gene, showed very different sensitivity to lithium. These findings thus provide a rationale to further analyze the biochemical bases for combined glucose deprivation and GSK-3β inhibition as a new approach to control transformed cell growth.
authors: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. decandiapaola@ingm.it
authors: Paola
authors: P
authors: de Candia
authors: Giuseppina
authors: G
authors: Minopoli
authors: Viola
authors: V
authors: Verga
authors: Anna
authors: A
authors: Gargiulo
authors: Marco
authors: M
authors: Vanoni
authors: Lilia
authors: L
authors: Alberghina
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D052756:Nutritional Sciences; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D001973:Bromodeoxyuridine; D005947:Glucose