C84
Regulation of cell death responses in hypoxia
Afshan Ahmed, Jun Yang, Margaret Ashcroft
University College London, London, UK
Hypoxia, defined as low oxygen tension, is a common characteristic of growing tumours. Cancer cells adapt to their hypoxic microenvironment by inducing angiogenesis and escaping cell death. In doing so, tumour cells become resistant to radiotherapy and many forms of chemotherapy.
Hypoxia signalling is mediated by the hypoxia-inducible factor (HIF) transcriptional complex. HIF has been shown to cross-talk to the p53 tumour suppressor protein and it is increasingly clear that a complex relationship exists between the angiogenic and apoptotic pathways involving a high level of control.
We aim to understand how cell death responses are regulated in tumour cells by HIF and p53, in normoxia and hypoxia. We have investigated the induction of p53 by the small molecule RITA. By a unique mechanism of action that is dependent on p53, RITA can induce significant cell death of hypoxic tumour cells. In addition, anti-angiogenic effects are achieved in vitro and in vivo by inhibition of HIF-1α and HIF target genes, including VEGF. We have discovered a critical kinase that contributes to the p53-dependent activity of this small molecule, and have performed a candidate siRNA screen to identify the kinase involved. Our studies reveal a novel mechanism of action for RITA with the potential to improve the therapeutic targeting of HIF and hypoxic tumours.
