A wealth of evidence suggests that proteins from prion protein (PrP) family contribute to tumorigenesis in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), breast cancer, glioblastoma, colorectal cancer, gastric cancer, melanoma, etc. It is well documented that PrP is a biomarker for PDAC, breast cancer, and gastric cancer. However, the underlying mechanisms remain unclear. The major reasons for cancer cell-caused patient death are metastasis and multiple drug resistance, both of which connect to physiological functions of PrP expressing in cancer cells. PrP enhances tumorigenesis by multiple pathways. For example, PrP existed as pro-PrP in most of the PDAC cell lines, thus increasing cancer cell motility by binding to cytoskeletal protein filamin A (FLNa). Using PDAC cell lines BxPC-3 and AsPC-1 as model system, we identified that dysfunction of glycosylphosphatidylinositol (GPI) anchor synthesis machinery resulted in the biogenesis of pro-PrP. In addition, in cancer cells without FLNa expression, pro-PrP can modify cytoskeleton structure by affecting cofilin/F-actin axis, thus influencing cancer cell movement. Besides pro-PrP, we showed that GPI-anchored unglycosylated PrP can elevate cell mobility by interacting with VEGFR2, thus stimulating cell migration under serum-free condition. Besides affecting cancer cell motility, overexpressed PrP or doppel (Dpl) in cancer cells has been shown to increase cell proliferation, multiple drug resistance, and angiogenesis, thus, proteins from PrP gene family by affecting important processes via multiple pathways for cancer cell growth exacerbating tumorigenesis.
Keywords: Cell motility; Doppel protein; Prion protein; Signal transduction; Tumorigenesis.