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 upregulated in multiple cancers. PrP expression in cancer cells contributes to cancer progression and resistance to various cancer therapies. Epigenetic changes in the gene expression and hyperactivation of MAP kinase signaling, 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 of the 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.

Figure 1. A schematic diagram showing the molecular interactions of the cellular prion protein (PrP)

The cellular prion protein (PrP) consists of 3 α-helical domains and a highly disordered but functionally conserved N-terminal domain that interacts with a number of key regulatory proteins of several pathways to promote cell survival and proliferation. PrP has been shown to directly bind the chaperone protein αβ-crystallin which could then promote cell cycle progression via de-repression of cyclin D1 and also via the conversion of the p53 tumor suppressor to a mutant conformation. PrP can inhibit the activation of both the extrinsic and intrinsic apoptotic pathways. It can potentially inhibit the activation of caspases and/or pro-apoptotic Bax and promote the stabilization of the pro-survival protein Bcl-2. PrP over-expression can also activate the PI3k/Akt pathway promoting cancer cell invasion and metastasis via increased expression of the matrix metalloproteinase 11 (MMP11). A putative prion infected mutant p53 could promote cell cycle progression and prevent apoptosis via the functional alteration of wild-type p53. Solid arrows in the figure indicate documented interactions from the literature and dashed arrows indicate hypothetical interactions proposed in this review.