Significance of Prion and Prion-Like Proteins in Cancer Development, Progression and Multi-Drug Resistance

Abstract

Prions are renowned for their role in neurodegenerative diseases in humans and animals. These are manifested as transmissible spongiform encephalopathies (TSEs) that result from the conversion of the normal glycosylphosphatidylinositol (GPI) anchored cellular prion protein (PrP(c)) to a misfolded, aggregated and pathogenic form, prion protein scrapie (PrP(Sc)) via a post-translational process followed by the accumulation of PrP(Sc) within the central nervous system. New research in this area has demonstrated that PrP is over-expressed in a variety of cancers including gastric, pancreatic and breast cancers, affecting the growth and invasiveness of these cancers as well as playing an important role in the acquisition of multi-drug resistant (MDR) gastric cancer. Prion-like doppel protein (Dpl), sharing 25% amino acid sequence homology to PrP and whose function remains elusive, has also been shown to exhibit a high level of expression in a number of cancers including acute myeloid leukemia's, myelodysplastic syndromes, gastric adenocarcinoma, anaplastic meningioma and astrocytomas. Furthermore, the tumour suppressor protein, p53, already known for its involvement in cancer development, has recently been shown to display prion-like tendencies. This review provides an overview of prions and prion-like proteins in mammals discussing their structure, function and role in cell function and disease. Furthermore, current research progress on the role of prion/prion-like proteins in the development, progression, and drug resistance of various cancers will be summarized. Potential implications for future development of new therapeutic treatments targeting prion and prion-like proteins will be discussed.

Prion protein regulates glutathione metabolism and neural glutamate and cysteine uptake via excitatory amino acid transporter 3

“…; Hinton et al . ). PrP is ubiquitously expressed by most, if not all cell types in mammals, and is a prominent protein in the brain (Prusiner ).…”

“…The pathogenic and infectious form of prion protein (PrP), the so-called scrapie form, plays a crucial role in the development of transmissible spongiform encephalopathies, such as Creutzfeldt-Jakob disease, Gerstmann-Str€ aussler-Scheinker syndrome, kuru and familial fatal insomnia, and is also involved in non-transmissible neurological disorders, such as Alzheimer's disease (Collinge 1997;Vana et al 2007). The cellular, non-pathogenic form of PrP has been implicated in protective functions against oxidative stress, hypoxia, ischemia, excitotoxicity, or hypoglycemia, and linked to disorders, such as schizophrenia, bipolar disorder, depression, certain forms of dementia with cerebellar disorder, and cancer (Raeber et al 1997;Walz et al 1999;Vassallo and Herms 2003;McLennan et al 2004;Roucou et al 2004;Weise et al 2004Weise et al , 2006Weise et al , 2008Shyu et al 2005;Spudich et al 2005;Weis et al 2008;Hinton et al 2013).…”

Analysis of the electrophoretic profiles of prion protein in carcinous and pericarcinous lysates of six different types of cancers

“…Overexpression of PrP is proposed to be closely associated with poor prognosis of pancreatic and breast cancers, highlighting that PrP may affect the growth and invasiveness of cancers. Study also has demonstrated an important role of overexpression of PrP in the acquisition of multi-drug resistant gastric cancer [8]. However, the profiles of PrP in malignant tumors, such as the patterns in electrophoresis and biochemistry features, are addressed little.…”

Expression of prion protein is closely associated with pathological and clinical progression and abnormalities of p53 in head and neck squamous cell carcinomas

“…Various studies have even proposed that overexpression of PrP is closely associated with the poor prognosis of pancreatic and breast cancers, highlighting that it may affect the growth and invasiveness of cancers (16). PrP expression is also believed to play an important role in the acquisition of multidrug-resistant (MDR) gastric cancer (17). However, the expression of PrP and its role in HNSCCs remain undescribed.…”