The Cellular Prion Protein: A Promising Therapeutic Target for Cancer

Abstract

Studies on the cellular prion protein (PrP^C) have been actively conducted because misfolded PrP^C is known to cause transmissible spongiform encephalopathies or prion disease. PrP^C 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 PrP^C mediates tumor progression by enhancing the proliferation, metastasis, and drug resistance of cancer cells. In addition, PrP^C regulates cancer stem cell properties by interacting with cancer stem cell marker proteins. In this review, we summarize how PrP^C 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 PrP^C via the regulation of HSPA1L/HIF-1α expression and using an anti-prion antibody.

Keywords: PRNP; PrPC; cancer; cancer stem cell; cellular prion protein; targeted cancer therapy.

Figure 1

Proteins and signaling pathways that seem to be affected by PrP^C expression. Various proteins and signaling pathways reportedly interact with or are modulated by PrP^C. Some of the proteins shown are known to be regulated indirectly through other proteins rather than direct interaction with PrP^C. PrP^C: prion protein, ECM: extracellular matrix, CSC: cancer stem cell.

Figure 2

Strategies to suppress the tumor progression by regulating the expression and function of PrP^C. (a) In tumor niche, the expression of HSPA1L is increased. HSPA1L binds and stabilizes HIF-1α. HSPA1L directly binds to GP78 and inhibits its ubiquitination activity. Overall, PrP^C expression is increased in tumor cells. Therefore, knocking down HSPA1L and HIF-1α expression induces degradation of PrP^C and tumor suppression. (b) Direct targeting of PrP^C using anti-PrP^C antibodies has been demonstrated as a potent cancer therapy. Anti-PrP^C antibody also can be used as a combination therapy with conventional anticancer drugs.