Mutant p53 as a guardian of the cancer cell

Mutant p53 promotes adaptive responses to cancer-related stress conditions to support tumor progression. Cancer cells in a growing tumor are exposed to multiple intrinsic and extrinsic stress conditions. Oncogenic p53 missense mutant forms (mutp53) can sense multiple stress inputs (blue), and act as homeostatic factors to induce adaptive mechanisms (red). Oxidative and proteotoxic stress: mutp53 has been shown to induce a pro-survival response to oxidative stress [45], to facilitate protein folding [69], and to increase proteasome activity [6, 66] in human cancer cell lines of breast, lung, and pancreatic origin. DNA lesions: mutp53 was shown to inhibit the DNA-damage response (DDR) in humanized mutp53 knock-in (HUPKI) mice [48, 49], to counteract autophagic cell death in breast cancer [25], and to inhibit therapy-induced apoptosis in head and neck cancer [55]. Altered metabolic requirements: mutp53 has been shown to sustain anabolic growth by enhancing glucose import and promoting the Warburg effect in mutp53 knock-in mice [34], and to modulate lipid metabolism in human breast cancer cell lines [42]. Hostile tumor microenvironment: mutp53 has been shown to modulate the extracellular milieu by promoting angiogenesis in breast cancer [73, 74], amplifying cancer-promoting inflammation in the colon of knock-in mice [79], and inducing a pro-invasive secretome in human lung tumors and derived cell lines [77