Potential roles for prions and protein-only inheritance in cancer

Abstract

Inherited mutations are known to cause familial cancers. However, the cause of sporadic cancers, which likely represent the majority of cancers, is yet to be elucidated. Sporadic cancers contain somatic mutations (including oncogenic mutations), however, the origin of these mutations is unclear. An intriguing possibility is that a stable alteration occurs in somatic cells prior to oncogenic mutations and promotes the subsequent accumulation of oncogenic mutations. This review explores the possible role of prions and protein-only inheritance in cancer. Genetic studies using lower eukaryotes, primarily yeast, have identified a large number of proteins as prions that confer dominant phenotypes with cytoplasmic (non-Mendelian) inheritance. Many of these have mammalian functional homologs. The human prion protein (PrP) is known to cause neurodegenerative diseases and has now been found to be up-regulated in multiple cancers. PrP expression in cancer cells contributes to cancer progression and resistance to various cancer therapies. Epigenetic changes in gene expression and hyper-activation of MAP kinase (MAPK) signalling, processes that in lower eukaryotes are affected by prions, play important roles in oncogenesis in humans. Prion phenomena in yeast appear to be influenced by stresses and there is considerable evidence for association of some amyloids with biologically positive functions. This suggests that if protein-only somatic inheritance exists in mammalian cells, it might contribute to cancer phenotypes. Here we highlight evidence in the literature for an involvement of prion or prion-like mechanisms in cancer and how they may in the future be viewed as diagnostic markers and potential therapeutic targets.

Mouse models of prostate cancer: picking the best model for the question

“…Extensive analysis of TRAMP mice has also revealed that they harbor AR single base substitution within their tumors, and the incidence of AR mutation increases with castration[54]. As one of the first models, TRAMP has been utilized to validate genes involved in PCa progression[55], as well as chemopreventative approaches and novel therapeutics[56]. …”

“…We would like to thank all researchers whose work we have cited, those whose contributions were omitted in the interest of space constraints, and those whose omission was unintentional. The brevity of this review is greatly attributable to the excellent and exhaustive reviews on mouse models[55,138-140], mouse PCa pathology[9,10], and human PCa progression[139] published previously.…”

The aggregation of mutant p53 produces prion-like properties in cancer

“…Wildtype p53 aggregates were shown to enter HeLa and NIH3T3 cells (most likely via macropinocytosis) and induce intracellular p53 aggregation. 13 In their review article, Antony et al 68 emphasized the likely role of protein-only inheritance and prions in cancer. Genetic studies with yeast showing that prions confer dominant phenotypes with cytoplasmic inheritance to these organisms indicate that several of these proteins have mammalian functional homologs.…”

The amyloid interactome: Exploring protein aggregation

“…Nevertheless, MCL algorithm results point toward a possible relationship between Clusterin and Aker or APrp, a finding that remains to be elucidated. Additional proteins of this cluster are associated with transcriptional regulation and pre-mRNA splicing, since the over-expression of prions influences normal cellular proteins, participating in apoptosis or cell signaling [104]. Transthyretin, a potent inhibitor of Aβ [72], created a separate cluster together with Small ubiquitin-related modifier 3.…”