LRP/LR as an alternative promising target in therapy of prion diseases, Alzheimer's disease and cancer.

The 37 kDa/67 kDa laminin receptor (LRP/LR) represents a key player for cell adhesion, is associated with the metastatic potential of solid tumors and is required for maintenance of cell viability by preventing apoptosis. LRP/LR acts as a receptor for viruses such as Sindbis virus, Venezuelean Equine Encephalitis (VEE) virus, Adeno-associated-viruses (AAV) and Dengue Virus, the latter causing 50 to 100 million infections in humans per year. LRP/LR acts further as a receptor for prions and represents a multifunctional protein subcellularly located to the nucleus, the cytoplasm and the cell surface. The receptor represents an alternative target for therapy of viral infections, cancer and prion disorders and might play additional roles in further neurodegenerative diseases such as Alzheimer's disease. The species barrier in prion disorders might be at least in part determined by the presence of LRP/LR in enterocytes of the intestinal epithelium. Anti-LRP/LR antibodies, siRNAs directed against LRP mRNA, polysulfated glycanes such as pentosan polysulfate and heparan mimetics and LRP decoy mutants are promising tools for blocking or downregulating the receptor and may represent alternative therapeutics for the treatment of prion disorders, Alzheimer's Disease and metastatic cancer.

Invasion of tumorigenic HT1080 cells is impeded by blocking or downregulating the 37-kDa/67-kDa laminin receptor.

The 37-kDa/67-kDa laminin receptor precursor/laminin receptor (LRP/LR) acting as a receptor for prions and viruses is overexpressed in various cancer cell lines, and their metastatic potential correlates with LRP/LR levels. We analyzed the tumorigenic fibrosarcoma cell line HT1080 regarding 37-kDa/67-kDa LRP/LR levels and its invasive potential. Compared to the less invasive embryonic fibroblast cell line NIH3T3, the tumorigenic HT1080 cells display approximately 1.6-fold higher cell-surface levels of LRP/LR. We show that anti-LRP/LR tools interfere with the invasive potential of HT1080 cells. Anti-LRP/LR single-chain variable fragment antibody (scFv) iS18 generated by chain shuffling from parental scFv S18 and its full-length version immunoglobulin G1-iS18 reduced the invasive potential of HT1080 cells significantly by 37% and 38%, respectively. HT1080 cells transfected with lentiviral plasmids expressing small interfering RNAs directed against LRP mRNA showed reduced LRP levels by approximately 44%, concomitant with a significant decrease in the invasive potential by approximately 37%. The polysulfated glycans HM2602 and pentosan polysulfate (SP-54), both capable of blocking LRP/LR, reduced the invasive potential by 20% and 35%, respectively. Adhesion of HT1080 cells to laminin-1 was significantly impeded by scFv iS18 and immunoglobulin G1-iS18 by 60% and 68%, respectively, and by SP-54 and HM2602 by 80%, suggesting that the reduced invasive capacity achieved by these tools is due to the perturbation of the LRP/LR-laminin interaction on the cell surface. Our in vitro data suggest that reagents directed against LRP/LR or LRP mRNA such as antibodies, polysulfated glycans, or small interfering RNAs, previously shown to encompass an anti-prion activity by blocking or downregulating the prion receptor LRP/LR, might also be potential cancer therapeutics blocking metastasis by interfering with the LRP/LR-laminin interaction in neoplastic tissues.