title: Accelerated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells.
abstract: Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a pivotal glycolytic enzyme, and a signaling molecule which acts at the interface between stress factors and the cellular apoptotic machinery. Earlier, we found that knockdown of GAPDH in human carcinoma cell lines resulted in cell proliferation arrest and chemoresistance to S phase-specific cytotoxic agents. To elucidate the mechanism by which GAPDH depletion arrests cell proliferation, we examined the effect of GAPDH knockdown on human carcinoma cells A549. Our results show that GAPDH-depleted cells establish senescence phenotype, as revealed by proliferation arrest, changes in morphology, SA-β-galactosidase staining, and more than 2-fold up-regulation of senescence-associated genes DEC1 and GLB1. Accelerated senescence following GAPDH depletion results from compromised glycolysis and energy crisis leading to the sustained AMPK activation via phosphorylation of α subunit at Thr172. Our findings demonstrate that GAPDH depletion switches human tumor cells to senescent phenotype via AMPK network, in the absence of DNA damage. Rescue experiments using metabolic and genetic models confirmed that GAPDH has important regulatory functions linking the energy metabolism and the cell cycle networks. Induction of senescence in LKB1-deficient non-small cell lung cancer cells via GAPDH depletion suggests a novel strategy to control tumor cell proliferation.
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
authors.forename: Manali
authors.initials: M
authors.lastname: Phadke
authors.forename: Natalia
authors.initials: N
authors.lastname: Krynetskaia
authors.forename: Anurag
authors.initials: A
authors.lastname: Mishra
authors.forename: Evgeny
authors.initials: E
authors.lastname: Krynetskiy
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D055785:Gene Knockdown Techniques; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: C403671:DELEC1 protein, human; D025521:Tumor Suppressor Proteins; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); C061901:GLB1 protein, human; D001616:beta-Galactosidase