Induction of intracellular wild-type p53 amyloids leading to cellular transformation and tumor formation in mice

Abstract

Tumor suppressor p53 mutations, with subsequent loss-of-tumor suppressive function and gainof oncogenic functions, are associated with more than 50% of human cancers. Aggregation and amyloid formation are also mechanisms by which wild type and mutant p53 might be involved in cancer, but the direct evidence of how aggregated p53 acts as an oncogene is lacking. In this study, we directly demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to normal cells. Cells with p53 amyloids show enhanced survival, apoptotic resistance with increased proliferation and migration rates. The tumorigenic potential of p53 amyloid transformed cells is further confirmed in a mice xenograft model, wherein the tumor showed p53 amyloid aggregates. Gene-expression analysis and proteomic profiling suggest that p53 amyloid formation triggers aberrant expression of pro-oncogenes while downregulating the tumorsuppressive genes. Interestingly, disaggregating p53 rescues the cellular transformation and also inhibits tumor development in mice. We propose that wild-type p53 amyloid formation can potentially contribute to the initiation of tumor development.

p53 amyloid pathology with cancer grades and p53 mutations

“…Recent data suggest that p53 aggregation and amyloid formation is also associated with the loss of p53 tumor suppressive function and the gain of oncogenic function (Ghosh et al, 2017). Moreover, our group has recently demonstrated that p53 amyloids have prion-like properties in cells and can induce cancerous transformation in normal cells (Navalkar et al, 2020a). Although previous data suggest that p53 amyloid might be associated with cancer, the extent of p53 amyloids and cancer disease severity (such as cancer grade) is still not established yet.…”