Article ; Online: Mitochondrial glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase abrogate p53 induced apoptosis in a yeast model: Possible implications for apoptosis resistance in cancer cells.
Biochimica et biophysica acta. General subjects
2019 Volume 1864, Issue 3, Page(s) 129504
Abstract: Background: Escape from apoptosis is an important hallmark of tumor progression and drug resistance in cancer cells. It is well demonstrated that over-expression of human wtp53 in Saccharomyces cerevisiae induces apoptosis by directly targeting the ... ...
Abstract | Background: Escape from apoptosis is an important hallmark of tumor progression and drug resistance in cancer cells. It is well demonstrated that over-expression of human wtp53 in Saccharomyces cerevisiae induces apoptosis by directly targeting the mitochondria. In this study, we showed that how S.cerevisiae escaped from p53 induced apoptosis in the presence of a fermentable carbon source (sucrose), but not on non-fermentable carbon source (glycerol). Methods: Mitochondrial fractions from yeast cultures grown in the presence of sucrose or glycerol with and without p53 expression were fractionated and analyzed by LC-MS/MS. Differentially expressed proteins were studied and detailed biochemical analysis for selected proteins was performed.The effect of mitochondrial HXK-2 over-expression induced by p53 in sucrose grown cells on cell survival was evaluated using gene deletion/tagging, co-localisation and mitochondrial ROS detection. Results: We observe that mitochondria isolated from p53 over-expressing cells accumulate Pentose phosphate Pathway (PPP) enzymes including glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) which led to enhanced mitochondrial NADPH production only when cells are cultured in sucrose but not glycerol. In contrast, mitochondria isolated from Δhxk2 p53 over-expressing cells grown in sucrose did not accumulate G6PDH and 6PGDH and resulted in defective growth. Conclusions: Enhanced association of HXK2 with the mitochondria with the concomitant accumulation of G6PDG and 6PGDH results in increased NADPH that scavenges ROS and provides resistance to apoptosis. General significance: Given the extensive similarity of aerobic glycolysis between humans and yeast, the phenomena described here could as well be responsible for the escape of apoptosis in cancer cells. |
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MeSH term(s) | Apoptosis/drug effects ; Apoptosis/physiology ; Chromatography, Liquid/methods ; Drug Resistance, Neoplasm/physiology ; Fermentation/physiology ; Glucose/metabolism ; Glucosephosphate Dehydrogenase/genetics ; Glucosephosphate Dehydrogenase/metabolism ; Glucosephosphate Dehydrogenase/pharmacology ; Glycerol/metabolism ; Hexokinase/genetics ; Hexokinase/metabolism ; Mitochondria/metabolism ; NADP/metabolism ; Phosphates/metabolism ; Phosphogluconate Dehydrogenase/genetics ; Phosphogluconate Dehydrogenase/metabolism ; Reactive Oxygen Species/metabolism ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Sucrose/metabolism ; Tandem Mass Spectrometry/methods ; Tumor Suppressor Protein p53/metabolism |
Chemical Substances | Phosphates ; Reactive Oxygen Species ; Saccharomyces cerevisiae Proteins ; Tumor Suppressor Protein p53 ; NADP (53-59-8) ; Sucrose (57-50-1) ; Phosphogluconate Dehydrogenase (EC 1.1.1.43) ; Glucosephosphate Dehydrogenase (EC 1.1.1.49) ; HXK2 protein, S cerevisiae (EC 2.7.1.1) ; Hexokinase (EC 2.7.1.1) ; Glucose (IY9XDZ35W2) ; Glycerol (PDC6A3C0OX) |
Language | English |
Publishing date | 2019-12-17 |
Publishing country | Netherlands |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 60-7 |
ISSN | 1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399 |
ISSN (online) | 1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650 |
ISSN | 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399 |
DOI | 10.1016/j.bbagen.2019.129504 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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