title: Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT.
abstract: Restoration of hypoxia-induced apoptosis in tumors harboring p53 mutations has been proposed as a potential therapeutic strategy; however, the transcriptional targets that mediate hypoxia-induced p53-dependent apoptosis remain elusive. Here, we demonstrated that hypoxia-induced p53-dependent apoptosis is reliant on the DNA-binding and transactivation domains of p53 but not on the acetylation sites K120 and K164, which, in contrast, are essential for DNA damage-induced, p53-dependent apoptosis. Evaluation of hypoxia-induced transcripts in multiple cell lines identified a group of genes that are hypoxia-inducible proapoptotic targets of p53, including inositol polyphosphate-5-phosphatase (INPP5D), pleckstrin domain-containing A3 (PHLDA3), sulfatase 2 (SULF2), B cell translocation gene 2 (BTG2), cytoplasmic FMR1-interacting protein 2 (CYFIP2), and KN motif and ankyrin repeat domains 3 (KANK3). These targets were also regulated by p53 in human cancers, including breast, brain, colorectal, kidney, bladder, and melanoma cancers. Downregulation of these hypoxia-inducible targets associated with poor prognosis, suggesting that hypoxia-induced apoptosis contributes to p53-mediated tumor suppression and treatment response. Induction of p53 targets, PHLDA3, and a specific INPP5D transcript mediated apoptosis in response to hypoxia through AKT inhibition. Moreover, pharmacological inhibition of AKT led to apoptosis in the hypoxic regions of p53-deficient tumors and consequently increased radiosensitivity. Together, these results identify mediators of hypoxia-induced p53-dependent apoptosis and suggest AKT inhibition may improve radiotherapy response in p53-deficient tumors.
authors.forename: Katarzyna B
authors.initials: KB
authors.lastname: Leszczynska
authors.forename: Iosifina P
authors.initials: IP
authors.lastname: Foskolou
authors.forename: Aswin G
authors.initials: AG
authors.lastname: Abraham
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Anbalagan
authors.forename: Céline
authors.initials: C
authors.lastname: Tellier
authors.forename: Syed
authors.initials: S
authors.lastname: Haider
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.forename: Eric E
authors.initials: EE
authors.lastname: O'Neill
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D013429:Sulfatases; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C518673:CYFIP2 protein, human; D002352:Carrier Proteins; D017874:Immediate-Early Proteins; C581867:KANK3 protein, human; D009687:Nuclear Proteins; C495901:TP53 protein, human; C109277:TSSC3 protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D015238:Sulfotransferases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; C470792:SULF2 protein, human; D013429:Sulfatases