Targeting Biomolecular Condensation and Protein Aggregation against Cancer

Abstract

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.

From a Droplet to a Fibril and from a Fibril to a Droplet: Intertwined Transition Pathways in Highly Dynamic Enzyme-Modulated Peptide-Adenosine Triphosphate Systems

“…Our results also imply that ATP not only serves as an energy source and controls protein homeostasis in living cells but also acts as a factor influencing LLPS formation and the LST of amyloidogenic peptides, an aspect that has received much attention recently . Furthermore, an in-depth analysis of the patterns of evolving intermolecular interactions underlying the dynamics of liquid phase separation, the condensates’ viscoelastic properties, and subsequent amyloidogenesis in complex multicomponent systems is urgently needed for the development of successful therapeutic targeting of the LLPS → amyloid pathway of various disease-linked proteins, such as mutated p53. − In this context, understanding the spatiotemporal dimension of the LST of condensates and how it is affected by small nucleotides like the abundant ATP and enzymes could provide clues for interventions to mitigate this transition when it drives such systems from physiological to pathological conditions.…”

Targeting misfolding and aggregation of the amyloid-β peptide and mutant p53 protein using multifunctional molecules

“…1–4 Example biomolecules include the amyloid-beta (Aβ) peptide and tau protein in Alzheimer's disease (AD), α-synuclein in Parkinson's, islet amyloid polypeptide (iAPP) in diabetes, TDP-43/TMEM106B in frontotemporal lobar degeneration, the prion protein in Creutzfeldt–Jakob disease, and the p53 protein in cancer. 5–10 In these cases, cellular and biochemical studies highlight that peptide/protein aggregation may play a significant role in disease progression. A number of critical advances have been made in our understanding of biomolecule misfolding, and this includes the development of imaging agents to track specific biomolecules in cells and in vivo .…”

“…The p53 protein is commonly regarded as ‘the guardian of the genome’ and is responsible for regulating critical processes such as apoptosis, DNA repair, and cell cycle arrest of damaged cells. 15,16 Unfortunately, the p53 protein is commonly mutated in cancer, 17 and mutations can lead to unfolding and aggregation to form insoluble amyloid deposits, 8 thereby compromising function. Thus, the development of small molecules capable of reactivating mutant p53 either by stabilizing the active folded form, and/or inhibiting aggregation hold considerable promise.…”

“…Stability mutants can result in conformational changes to the p53 protein that perturb Zn-binding and DNA interactions (R175H, R282Q), and generally result in a loss of function due to decreased stability, aggregation, and amyloid formation (G245S, R248Q, R249S, R282W and Y220C). 8,143,144…”

“…Molecules have been reported that inhibit the aggregation process and/or break up insoluble aggregates as a means to reactivate the p53 pathway. 8,144,180 In an innovative development, Eisenberg et al 181 reported a cell-penetrating peptide ReACp53 (Fig. 17) which was shown to interact with the aggregation-prone 252–258 segment (LTIITLE, see pink ribbon Fig.…”