Role of p53 in overcoming tumour therapy resistance

Since the discovery of p53 by David Lane and colleagues in the 1970's, this tumour suppressor gene has emerged as one of most important molecules in suppressing cancer development and progression. There is little surprise therefore that p53 undergoes loss-of-function mutations in over 50% of solid tumours including lung, colon and breast cancers. mutations in p53 alone or in combination with loss-of-function in other tumour suppressors can confer resistance to chemo- and radiotherapy, the main mechanisms of which are to induce a DNA damage response that leads to cell death and senescence.

 The role of p53 in mediating apoptosis and cell cycle arrest following DNA damage and cell stress is well established but a recent paper has highlighted an additional mode of action. p53 activation in normal (non-tumour) cells resulted in suppression of UACA, a molecule involved in the sequestration and degradation of PAR-4. The release of pro-apoptotic PAR-4 from these p53-proficient normal cells was able to act in paracrine (local) and systemic fashion to induce selective tumour cell death for in vitro and in vivo models of p53-deficient prostate and lung cancers (1).

The above study is interesting on several fronts. Firstly and most importantly, this study raises the possibility of using synthetic PAR-4 analogues and UACA inhibitors in the treatment of  solid tumour types in a manner that targets one of the most common genetic defects. Further studies elucidating the pathways utilised by PAR-4 when it interacts with tumour cells may help in defining cross-talk with other pathways which are deregulated, giving scope to multi-agent targeting to achieve a synergistic effect. Further studies in other solid tumour types will also help to validate these findings. A second point which the above study illustrates is that despite extensive research on p53, new modes of action are constantly emerging which demonstrate we are only at the tip of the iceberg when it comes to understanding 'the guardian of the genome'.

Reference

Burikhanov et al. Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4 Cell Reports (2014) to be found here