Cellular Prion Protein: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Sang Hun Lee.

Studies on the cellular prion protein (PrPC) have been actively conducted because

misfolded PrPC is known to cause transmissible spongiform encephalopathies or prion disease. PrPC

is a glycophosphatidylinositol‐anchored cell surface glycoprotein that has been reported to affect

several cellular functions such as stress protection, cellular differentiation, mitochondrial

homeostasis, circadian rhythm, myelin homeostasis, and immune modulation. Recently, it has also

been reported that PrPC mediates tumor progression by enhancing the proliferation, metastasis, and

drug resistance of cancer cells. In addition, PrPC regulates cancer stem cell properties by interacting

with cancer stem cell marker proteins. In this review, we summarize how PrPC promotes tumor

progression in terms of proliferation, metastasis, drug resistance, and cancer stem cell properties. In

addition, we discuss strategies to treat tumors by modulating the function and expression of PrPC

via the regulation of HSPA1L/HIF‐1α expression and using an anti‐prion antibody.

Studies on the cellular prion protein (PrPC) have been actively conducted because misfolded PrPC is known to cause transmissible spongiform encephalopathies or prion disease. PrPC is a glycophosphatidylinositol‐anchored cell surface glycoprotein that has been reported to affect several cellular functions such as stress protection, cellular differentiation, mitochondrial homeostasis, circadian rhythm, myelin homeostasis, and immune modulation. Recently, it has also been reported that PrPC mediates tumor progression by enhancing the proliferation, metastasis, and drug resistance of cancer cells. In addition, PrPC regulates cancer stem cell properties by interacting with cancer stem cell marker proteins. In this review, we summarize how PrPC promotes tumor progression in terms of proliferation, metastasis, drug resistance, and cancer stem cell properties. In addition, we discuss strategies to treat tumors by modulating the function and expression of PrPC via the regulation of HSPA1L/HIF‐1α expression and using an anti‐prion antibody.

  • Cancer, PRNP, PrPC, prion protein,

Note：All the information in this draft can be edited by authors. And the entry will be online only after authors edit and submit it.

1. Introduction

The cellular prion protein (PrPC) is a cell surface glycophosphatidylinositol (GPI)-anchored protein consisting of 208 amino acids, and it is encoded by the PRNP gene located on chromosome 20. PrPC has been intensively studied since it was proposed that misfolding of PrPC plays a key role in the pathogenesis of neurodegenerative diseases called transmissible spongiform encephalopathies [1–3][1][2][3]. Studies have shown that PrPC is not simply a cause of neurodegenerative diseases, but it is an important protein involved in many cellular functions such as stress protection, cellular differentiation, mitochondrial homeostasis, circadian rhythm, myelin homeostasis, and immune modulation [4–10][4][5][6][7][8][9][10]. Furthermore, several studies have shown that PrPC expression is associated with tumor progression [11–15][11][12][13][14][15]. Before addressing the role of PrPC in tumor progression, we briefly introduce herein some biochemical aspects of PrPC.

PrPC is first synthesized as a precursor protein (pre-pro-PrP) comprising 253 amino acids with a signal peptide at the N-terminus and a GPI anchor peptide signaling sequence (GPI-PSS) at the C-terminus. The signal peptide directs pre-pro-PrP into the endoplasmic reticulum (ER), wherein it is cleaved to generate pro-PrP. The pro-PrP is then translocated from the ER to the Golgi complex [16,17][16][17] to be further processed by the addition of N-linked glycans, removal of the GPI-PSS, and addition of the pre-assembled GPI anchor [18,19][18][19]. Finally, the mature PrPC of 208 amino acids is translocated to the outer membrane leaflet of cells. However, not all PrPCs are present on the cell surface. They are constantly internalized through the recycling endosome and trafficked back repeatedly [20–22][20][21][22]. Through this recycling process, PrPCs are also found in the Golgi [22[22][23],23], in addition to the nucleus [24,25][24][25] and mitochondria [26,27][26][27].

The relationship between PrPC and cancer progression was first discovered when PRNP was identified as one of the most-expressed genes in pancreatic cancer cells [28]. Around the same time, other researchers found that PrPC was overexpressed in a drug-resistant cancer cell line compared to the parental cell line [29]. Based on several studies, it is now well established that PrPC is involved in the main aspects of cancer biology: proliferation, metastasis, and drug resistance. Moreover, the relationship between PrPC and cancer stem cell phenotypes has also been uncovered [30,31][30][31].

2. Overview of Physiological Functions of PrPC

PrPC is known to regulate several functions of cells, such as stress protection, cellular differentiation, mitochondrial homeostasis, circadian rhythm, myelin homeostasis, and immune modulation. In this review, we briefly summarize the effects of PrPC on stress protection, cellular differentiation, and mitochondrial homeostasis.

Several studies have shown that PrPC can directly inhibit apoptosis. PrPC expression inhibited mitochondria-dependent apoptosis in Bax-overexpressing human primary neurons and MCF-7 breast cancer cells [32,33][32][33]. In addition, downregulation of PrPC reduced the viability of MDA-MB-435 breast cancer cells after serum deprivation [34]. In primary hippocampal neurons, PrPC protected the cells against staurosporine-induced cell death by interacting with stress-induced phosphoprotein 1 (STI1) [35–37][35][36][37]. PrPC is also known to protect cells from oxidative stress. For example, the basal levels of ROS and lipid peroxidation were lower in PrPC-transfected neuroblastoma and epithelial cell lines than in untransfected controls [38,39][38][39]. In addition, the expression of PrPC by primary neurons and astrocytes has been associated with lower levels of damage caused by the addition of various oxidative toxins such as xanthine oxidase, kainic acid, and hydrogen peroxide [40,41][40][41]. PrPC has also been found to be involved in the ER-stress response. When breast carcinoma cells were treated with the ER-stress inducing compounds such as brefeldin A, tunicamycin, and thapsigargin, the expression of PrPC was induced. Downregulation of PrPC in several cancer cell lines resulted in an increase in cell death in response to these toxins [13].

Neurite outgrowth is one of the characteristics of neuronal differentiation. Several studies have indicated that PrPC promotes neurite outgrowth through interactions with other proteins such as neural cell adhesion molecule 1, epidermal growth factor receptor, integrins, laminin, and STI1 [35,42–45][35][42][43][44][45]. The downstream signaling of these interactions may include RhoA-Rho kinase-LIMK-cofilin pathway [44]. Activation of various signal pathways, including extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol-3-kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs), may also induce PrPC-dependent neurite outgrowth [35,43,46][35][43][46]. It has been reported that PrPC is also involved in the differentiation of embryonic stem cells. In human embryonic stem cells, downregulation of PrPC delays spontaneous differentiation into the three germ layers [47]. Similarly, PrPC expression promotes the differentiation of cultured human embryonic stem cells and multipotent neural precursors to mature neurons, astroglia, and oligodendroglia [47,48][47][48].

PrPC expression also affects mitochondrial homeostasis. Transcriptomic and proteomic analyses of brain tissues and neurons of PrPC-null and wild-type mice have identified differently expressed proteins. These proteins include cytochrome c oxidase subunits 1 and 2, which are involved in oxidative phosphorylation [49,50][49][50]. Furthermore, the absence of PrPC reduces the number of total mitochondria and increases the number of mitochondria with unusual morphology [49].

3. PrPC and Cancer Proliferation

PrPC expression has been reported to promote cancer proliferation in several types of cancer cells, including gastric [51], pancreatic [52], and colon [53–55][53][54][55], as well as in glioblastoma (GBM) [56,57][56][57] and schwannanoma [58].

In gastric cancer, PrPC promotes cell proliferation and metastasis of cancer cells and promotes tumor growth in xenograft mouse models [51]. PrPC increases the expression of cyclin D1 and thereby promotes their transition from the G0/G1 phase to the S-phase. PrPC expression also affects Akt signaling. Overexpression of PrPC increases p-Akt levels, whereas PrPC knockdown inhibits p-Akt expression [59]. Interestingly, it is known that certain regions of PrPC influence cell proliferation. Specifically, deletion of amino acids 24–50 of PrPC significantly reduced cell proliferation. Conversely, deletion of amino acids 51–91 did not affect apoptosis, metastasis cell proliferation, and multidrug resistance in gastric cancer [60].

In pancreatic ductal adenocarcinoma (PDAC), expression of PrPC increases the proliferation and migration of the cells. In PDAC cell lines, PrPC exists as a pro-PrP as it retains its GPI-PSS, which has a filamin A (FLNA) binding motif. It was found that the interaction between pro-PrP and FLNA, a cytoplasmic protein involved in actin organization, promotes cell migration [61]. In addition, other studies have shown that PrPC promote pancreatic cell proliferation by activating the Notch signaling pathway [62].

PrPC is known to interact with other membrane proteins or extracellular molecules to perform various cellular functions. In human GBM, PrPC and heat shock 90/70 organizing protein (HOP) are upregulated, and their expression levels correlate with higher proliferation rates and poorer clinical outcomes [56]. Additionally, it has been demonstrated that the binding of HOP to PrPC promotes proliferation of GBM cell lines and that disruption of PrPC–HOP interaction inhibits tumor growth and improves the survival of mice [56].

In DLS-1 and SW480 colorectal cancer cells, knockdown of PrPC significantly reduces the proliferation of cancer cells. It is known that the binding between HIF-2α and the GLUT1 promoter region decreases when PrPC expression is suppressed, resulting in a decrease in the expression of GLUT1. This may reduce glucose uptake and glycolysis and inhibit cell proliferation [54].

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