Download HYPOXIA-INDUCED p53-DEPENDENT APOPTOSIS IS RELIANT

HYPOXIA-INDUCED p53-DEPENDENT APOPTOSIS IS RELIANT ON
TRANSACTIVATION OF CLINICALLY RELEVANT TARGET GENES
INCLUDING NEGATIVE REGULATORS OF AKT
Katarzyna B. Leszczynska1, Aswin G. Abraham1, Iosifina P. Foskolou1, Selvakumar
Anbalagan1, Céline Tellier1, Syed Haider1, Paul N. Span2, Eric O’Neill1, Francesca
M. Buffa1 and Ester M. Hammond1$
1
Cancer Research UK and Medical Research Council Oxford Institute for Radiation
Oncology, Department of Oncology, The University of Oxford, Oxford, OX3 7DQ,
UK, 2Radboud University Medical Centre, Department of Radiation Oncology 874,
PO Box 9101, 6500 HB Nijmegen, the Netherlands.
[email protected]
Most if not all solid tumors have regions of hypoxia. This is significant as tumor
hypoxia predicts treatment response regardless of the therapeutic modality used.
Restoring hypoxia induced apoptosis to p53 mutated tumors is an attractive
therapeutic strategy. We show that hypoxia-induced p53-dependent apoptosis is
dependent 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. We have identified and validated hypoxiainducible pro-apoptotic targets of p53. These include PHLDA3, and the novel target,
INPP5D, both of which mediate apoptosis through AKT inhibition. This led us to
demonstrate that pharmacological inhibition of AKT leads to apoptosis in hypoxia in
vitro and in vivo in cells lacking functional p53. Analysis of thousands of human
cancer samples, from independently curated sources, provides strong evidence that
these hypoxia-induced genes are regulated by p53 in human cancers, and that lack of
expression results in poorer patient prognosis, suggesting a crucial role for hypoxiainduced apoptosis in p53-mediated tumor suppression.