title: Differential effect of hypoxia on etoposide-induced DNA damage response and p53 regulation in different cell types.
abstract: Among the main causes of cancer cell resistance to chemotherapy are p53 mutation and hypoxic tumor microenvironment. However, the effect of hypoxia can be very different from one cell type to the other. We studied the effect of hypoxia on the etoposide-induced cell death in two cancer cell lines, HepG2 and A549 cells. Hypoxia decreased etoposide-induced apoptosis in HepG2 cells but not in A549 cells. Here, we evidenced two pathways, known to play important roles in cancer cell resistance, that are differently affected by hypoxia in these two cell types. First, in HepG2 cells, hypoxia decreased p53 protein level and activity by acting post-transcriptionally and independently of HIF-1. The results suggest an effect of hypoxia on p53 translation. On the other hand, in A549 cells, no effect of hypoxia was observed on p53 level. Secondly, hypoxia decreased DNA damage response in HepG2 cells while this was not the case in A549 cells. Indeed, a decrease in the phosphorylation level of CHK2 and H2AX with a decrease in ATM activity was observed. Importantly, these results evidenced that hypoxia can prevent cancer cell apoptosis by acting at different levels in the cell and that these effects are strongly cell-type dependent.
authors.affiliation: Laboratory of Biochemistry and Cellular Biology (URBC), NARILIS, University of Namur, Namur, Belgium.
authors.forename: Audrey
authors.initials: A
authors.lastname: Sermeus
authors.forename: Magali
authors.initials: M
authors.lastname: Rebucci
authors.forename: Maude
authors.initials: M
authors.lastname: Fransolet
authors.forename: Lionel
authors.initials: L
authors.lastname: Flamant
authors.forename: Déborah
authors.initials: D
authors.lastname: Desmet
authors.forename: Edouard
authors.initials: E
authors.lastname: Delaive
authors.forename: Thierry
authors.initials: T
authors.lastname: Arnould
authors.forename: Carine
authors.initials: C
authors.lastname: Michiels
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology*; D056945:Hep G2 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: C468783:H2AX protein, human; C497442:HIF1A protein, human; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human