Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4

•Activation of p53 function in normal cells for paracrine apoptosis of cancer cells•p53 recruits another tumor suppressor, Par-4, to execute its paracrine function•Identification of small molecules with specific targets as Par-4 secretagogues•UACA sequesters and inhibits Par-4 secretion

SummaryThe guardian of the genome, p53, is often mutated in cancer and may contribute to therapeutic resistance. Given that p53 is intact and functional in normal tissues, we harnessed its potential to inhibit the growth of p53-deficient cancer cells. Specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. This paracrine effect was mediated by p53-dependent secretion of the tumor suppressor Par-4. Accordingly, the activation of p53 in normal mice, but not p53−/− or Par-4−/− mice, caused systemic elevation of Par-4, which induced apoptosis of p53-deficient tumor cells. Mechanistically, p53 induced Par-4 secretion by suppressing the expression of its binding partner, UACA, which sequesters Par-4. Thus, normal cells can be empowered by p53 activation to induce Par-4 secretion for the inhibition of therapy-resistant tumors.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide