Unveiling a role for mutant p53 in regulation of Unfolded Protein Response

Disturbances in the homeostasis of endoplasmic reticulum (ER) referred to as ER stress is involved in a variety of human diseases. Tumor progression is strictly related to ER stress, while cancer cells are prone to tolerate unfolded protein accumulation and to take advantages from ER stress-related pro-survival pathways. Mutation of Tp53 gene is a frequent event in human tumor and a significant factor in cancer development and progression. We report that cancer cells bearing mutant p53 respond to ER stress insult by dampening ER-stress associated pro-apoptotic factor and by sustaining survival. Mechanistically, we find that mutp53 is inhibiting JNK and CHOP and is promoting ATF6 transcriptional activity. These observations reveals a protective role of mutant p53 in the response to chronic ER stress, offering an additional perspective to cancer treatment. Indeed, we observed a cooperative effect in using mutp53 and ATF6 inhibitors in killing cancer cells.