title: Advanced glycation end products (AGE) potentiates cell death in p53 negative cells via upregulaion of NF-kappa B and impairment of autophagy.
abstract: Accumulation of advanced glycation end products (AGE) in diabetic patients and ageing people due to excess availability of simple 3- or 4-carbon sugars, is well-known. AGE has multiple deleterious effects including age-related disorders, apoptosis, inflammation, and obesity. We have found that AGE increases autophagy but the sustained amount of autophagosomes is observed till 3 days without maturation. It is important to understand the underlying mechanism of AGE-mediated signaling responsible for impairment of autophagy and its correlation to the induction of several adverse effects. We have identified cross talk between autophagy and apoptosis upon AGE stimulation, specifically in p53 negative cells. AGE impairs autophagosomes' clearance in p53 negative cells as observed with an autophagosome maturation blocker-bafilomycinA1 treated cells. This autophagy impairment is well supported by upregulation and overexpression of NF-κB in these p53 negative cells. Autophagy impairment acts as a switch to initiate apoptosis via regulation of NF-κB and its dependent genes. Increase in the expression of NF-κB-dependent NEDD4, an E3 ubiquitin ligase, which targets Beclin1 for cleavage is also evident. Beclin1 interacts with Bcl-2, an anti-apoptotic protein thereby engaging it to facilitate apoptosis upon AGE stimulation. For the first time, we are providing data that NF-κB targeted cell signaling is involved in AGE-mediated autophagy impairment in p53 negative/null cells. The p53 acts antagonistically to prevent this impairment. This study will help to control the AGE-mediated detrimental effects associated with ageing and lysosomal storage disorders.
authors.affiliation: Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.|Graduate Studies, Manipal University, Manipal, Karnataka, India.
authors.forename: Neeharika
authors.initials: N
authors.lastname: Verma
authors.affiliation: Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
authors.forename: Sunil K
authors.identifier: http://orcid.org/0000-0002-0149-209X
authors.initials: SK
authors.lastname: Manna
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1 / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D020298:U937 Cells; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; D056827:Endosomal Sorting Complexes Required for Transport; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; D017239:Paclitaxel
keywords: Beclin1; NEDD4; NF-κB; apoptosis; autophagy impairment; p53; p62