Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT

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 apoptos...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	The Journal of clinical investigation Jg. 125; H. 6; S. 2385
Hauptverfasser:	Leszczynska, Katarzyna B, Foskolou, Iosifina P, Abraham, Aswin G, Anbalagan, Selvakumar, Tellier, Céline, Haider, Syed, Span, Paul N, O'Neill, Eric E, Buffa, Francesca M, Hammond, Ester M
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Society for Clinical Investigation 01.06.2015
Schlagworte:	Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Apoptosis Biomedical research Breast cancer Carrier Proteins - genetics Carrier Proteins - metabolism Cell Hypoxia - genetics Cell Line, Tumor DNA damage Humans Immediate-Early Proteins - genetics Immediate-Early Proteins - metabolism Inositol Polyphosphate 5-Phosphatases Mutation Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology Nuclear Proteins - genetics Nuclear Proteins - metabolism Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases Phosphoric Monoester Hydrolases - genetics Phosphoric Monoester Hydrolases - metabolism Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Radiation Tolerance Rodents Studies Sulfatases Sulfotransferases - genetics Sulfotransferases - metabolism Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism
ISSN:	0021-9738, 1558-8238, 1558-8238
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	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.
Bibliographie:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI80402