Gain-of-function mutant p53 enhances mitochondrial ROS through the inhibition of PGC-1α/UCP2 axis in cancer cells

Mutations in the TP53 gene occur in over 50% of the human cancers and most of them are missense mutations that result in the expression of mutant forms of p53. In addition, p53 mutated proteins acquire new biological properties referred as gain-of-function (GOF) that contribute to the induction and maintenance of cancer. Reactive oxygen species (ROS) are radicals, ions or molecules highly reactive that are produced as an inevitable byproduct of mitochondrial oxidative phosphorylation. ROS can act as second messengers in cellular signaling in human cancer and are implicated in a plethora of biological events addressed to sustain each aspect of its progression. Uncoupling protein 2 (UCP2) is located in the mitochondrial inner membrane and plays an essential role is critical in energy regulation and in the maintenance of cellular ROS homeostasis by limiting the production of mitochondrial superoxide. We have investigated the molecular mechanisms by which mutant p53 regulates the redox status in cancer cells and its role in sustaining cancer progression and chemoresistance. We found that mutant p53 proteins, contrarily to wild type p53, enhance mitochondrial ROS in cancer cells which are crucial mediators of their oncogenic activity leading: i) cancer cell proliferation, ii) inhibition of apoptosis, and iii) chemoresistance. Importantly, we unveiled that mutant p53 inhibits SESN/AMPK-α interaction leading an inhibition of AMPK phosphorylation. Consequently to the deregulation of AMPK signaling by mutant p53, but not by wild type p53, the expression of its effector PGC-1α was also affected, driving a reduction of UCP2 expression and an increase of mitochondrial superoxide. These data reveal a novel mechanism by which mutant p53 sustains tumor progression and lightened on the importance that plays the redox cellular status in the tumors carrying oncogenic mutant p53 proteins.