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Targeting Biomolecular Condensation and Protein Aggregation against Cancer

Lookup NU author(s): Professor Tiago OuteiroORCiD


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© 2023 American Chemical Society. Biomolecular condensates, membrane-less entities arising from liquid-liquid phase separation, hold dichotomous roles in health and disease. Alongside their physiological functions, these condensates can transition to a solid phase, producing amyloid-like structures implicated in degenerative diseases and cancer. This review thoroughly examines the dual nature of biomolecular condensates, spotlighting their role in cancer, particularly concerning the p53 tumor suppressor. Given that over half of the malignant tumors possess mutations in the TP53 gene, this topic carries profound implications for future cancer treatment strategies. Notably, p53 not only misfolds but also forms biomolecular condensates and aggregates analogous to other protein-based amyloids, thus significantly influencing cancer progression through loss-of-function, negative dominance, and gain-of-function pathways. The exact molecular mechanisms underpinning the gain-of-function in mutant p53 remain elusive. However, cofactors like nucleic acids and glycosaminoglycans are known to be critical players in this intersection between diseases. Importantly, we reveal that molecules capable of inhibiting mutant p53 aggregation can curtail tumor proliferation and migration. Hence, targeting phase transitions to solid-like amorphous and amyloid-like states of mutant p53 offers a promising direction for innovative cancer diagnostics and therapeutics.

Publication metadata

Author(s): Silva JL, Foguel D, Ferreira VF, Vieira TCRG, Marques MA, Ferretti GDS, Outeiro TF, Cordeiro Y, de Oliveira GAP

Publication type: Review

Publication status: Published

Journal: Chemical Reviews

Year: 2023

Volume: 123

Issue: 14

Pages: 9094-9138

Print publication date: 26/07/2023

Online publication date: 28/06/2023

Acceptance date: 01/03/2023

ISSN (print): 0009-2665

ISSN (electronic): 1520-6890

Publisher: American Chemical Society


DOI: 10.1021/acs.chemrev.3c00131