The tumor suppressor protein PTEN undergoes amyloid-like aggregation in tumor cells

Abstract

Protein aggregation is an underappreciated mechanism that may contribute to the loss- and oncogenic-gain-of-function of mutant tumor suppressors such as p53 and axin. In the present study, we describe amyloid-like aggregation behaviour of the second most frequently mutated tumor suppressor in human cancer, PTEN. In silico analysis revealed a particularly high aggregation vulnerability for this protein, which was corroborated by in vitro aggregation assays. In cultured tumor cells, we found that under stress conditions, PTEN readily undergoes amyloid-like aggregation as a result of mutation. However, we also show that severe dysregulation of protein homeostasis may lead to aggregation of wild-type PTEN. These observations were supported by a small survey of patient-derived uterine tumor tissues, which found that more than 25% of tumors analyzed displayed wild-type PTEN aggregation. Finally, in an exploratory clinical study we found that PTEN aggregation status was correlated with a decline in clinical outcome. Our findings establish that the tumor suppressor PTEN is highly aggregation-prone and our work suggests that protein aggregation might be an underestimated but prevalent component of cancer cell biology.

Cryptic amyloidogenic regions in intrinsically disordered proteins: Function and disease association

“…These functions entail binding to multiple targets and participation in PPI networks which, according to our analysis, would imply the presence of CARs, thus justifying the observed enrichments. Recent reports exploring the role of protein aggregation in tumor formation suggest that it may be an underestimated mechanism of loss of tumor-suppressing activity and oncogenic gain-of-function [98] , [99] , [100] , [101] , [102] .…”

p53 amyloid aggregation in cancer: function, mechanism, and therapy

“…During tumor cell culture, protein homeostasis is severely dysregulated under stressful conditions, and mutant PTEN is prone to amyloid aggregation, similar to wild-type PTEN [ 122 , 123 ]. In a small survey, aggregation was found in more than 25% of uterine tumor tissues, and PTEN aggregation status was negatively correlated with survival [ 124 ]. The retinoblastoma tumor suppressor (RB) also has aggregation properties.…”

Synuclein Proteins in Cancer Development and Progression

“…Like αS and γS, p53 was described to be transmitted between cells in a prion-like mechanistic fashion [91]. After the discovery of p53 aggregation, other potentially cancerrelated proteins were shown to aggregate, such as PTEN, p63, and p71 [92,93]. The question of the impact of protein aggregation in cancer is a research field currently growing, as new reports are connecting aggregation patterns with tumor treatment resistance, tumor progression, and metastasis development [94][95][96].…”