p53 and autophagy in cancer: guardian of the genome meets guardian of the proteome.

This review provides a summary of the European Association for Cancer Research 'Cancer Researcher Award' lecture which was presented at the EACR21 meeting in Oslo, Norway, in July 2010. The review focuses on the importance of programmed cell death regulation in tumour development and cancer therapy. Eradication of damaged cells is a principal mechanism of protection against cancer and involves key tumour suppressor proteins such as p53. Cell death-associated tumour suppressors, including p53, are often inactivated during the genesis of cancer and this poses problems for many forms of therapy which require these death proteins for a therapeutic response. The identification therefore of other factors and pathways that regulate cell viability is of prime importance for the development of rationalised new strategies to invoke tumour cell death. Historically, studies of programmed cell death in cancer have focused on the evolutionarily conserved process of apoptosis. More recently, however, attention has also turned to another process termed 'autophagy' which has profound effects on cell viability. Principally, autophagy serves to traffic damaged proteins and organelles to the lysosome for degradation. It functions therefore as a homeostatic mechanism that impinges on both protein and genome integrity. Summarized here are our findings linking p53 to autophagy and how this led to the identification of the human Damage-Regulated Autophagy Modulator (DRAM) family. Further discussion relates to our subsequent studies, together with those of others, that have yielded insights into the selective targeting of autophagy for the treatment of malignant disease.