Abstract
Missense mutations in the TP53 gene are frequent in human cancers, giving rise to mutant p53 proteins that can acquire oncogenic properties. Gain of function mutant p53 proteins can enhance tumour aggressiveness by promoting cell invasion, metastasis and chemoresistance. Accumulating evidences indicate that mutant p53 proteins can also modulate cell homeostatic processes, suggesting that missense p53 mutation may increase resistance of tumour cells to intrinsic and extrinsic cancer-related stress conditions, thus offering a selective advantage. Here we provide evidence that mutant p53 proteins can modulate the Unfolded Protein Response (UPR) to increase cell survival upon Endoplasmic Reticulum (ER) stress, a condition to which cancer cells are exposed during tumour formation and progression, as well as during therapy. Mechanistically, this action of mutant p53 is due to enhanced activation of the pro-survival UPR effector ATF6, coordinated with inhibition of the pro-apoptotic UPR effectors JNK and CHOP. In a triple-negative breast cancer cell model with missense TP53 mutation, we found that ATF6 activity is necessary for viability and invasion phenotypes. Together, these findings suggest that ATF6 inhibitors might be combined with mutant p53-targeting drugs to specifically sensitise cancer cells to endogenous or chemotherapy-induced ER stress.
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Acknowledgements
We thank Giada Pastore (LNCIB, Trieste) for assistance with tissue culture. We thank Ciara Gallagher and Peter Walter (UCSF, USA) for kindly providing Ceapin-A7. We thank all people from LNCIB (Trieste) for advice and discussion. This work was funded by AIRC (Italian Association for Cancer Research) Investigator Grant (IG 14173) to LC, and AIRC Special Program Molecular Clinical Oncology “5 per mille” (Grant no. 10016) to GDS. This work was also funded by Regione FVG (LR 17/2014; project acronym RIFT) to GDS. AB was supported by a “G. Lucatello e G. Mazzega” postdoctoral fellowship from FIRC (Fondazione Italiana Ricerca sul Cancro), and by a Fondazione Umberto Veronesi postdoctoral fellowship. MF was supported by a “L. Fontana and M. Lionello” fellowship from FIRC. EV was supported by a “G. Lucatello e G. Mazzega” postdoctoral fellowship from FIRC.
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Sicari, D., Fantuz, M., Bellazzo, A. et al. Mutant p53 improves cancer cells’ resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6. Oncogene 38, 6184–6195 (2019). https://doi.org/10.1038/s41388-019-0878-3
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DOI: https://doi.org/10.1038/s41388-019-0878-3
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