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The 37/67 kDa laminin receptor (LR) inhibitor, NSC47924, affects 37/67 kDa LR cell surface localization and interaction with the cellular prion protein.

ABSTRACT: The 37/67 kDa laminin receptor (LR) is a non-integrin protein, which binds both laminin-1 of the extracellular matrix and prion proteins, that hold a central role in prion diseases. The 37/67 kDa LR has been identified as interactor for the prion protein (PrP(C)) and to be required for pathological PrP (PrP(Sc)) propagation in scrapie-infected neuronal cells, leading to the possibility that 37/67 kDa LR-PrP(C) interaction is related to the pathogenesis of prion diseases. A relationship between 37/67 kDa LR and PrP(C) in the presence of specific LR inhibitor compounds has not been investigated yet. We have characterized the trafficking of 37/67 kDa LR in both neuronal and non-neuronal cells, finding the receptor on the cell surface and nuclei, and identified the 67 kDa LR as the almost exclusive isoform interacting with PrP(C). Here, we show that the treatment with the 37/67 kDa LR inhibitor, NSC47924, affects both the direct 37/67 kDa LR-PrP(C) interaction in vitro and the formation of the immunocomplex in live cells, inducing a progressive internalization of 37/67 kDa LR and stabilization of PrP(C) on the cell surface. These data reveal NSC47924 as a useful tool to regulate PrP(C) and 37/67 kDa LR trafficking and degradation, representing a novel small molecule to be tested against prion diseases.

SUBMITTER: Sarnataro D

PROVIDER: S-EPMC4829897 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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The 37/67 kDa laminin receptor (LR) inhibitor, NSC47924, affects 37/67 kDa LR cell surface localization and interaction with the cellular prion protein.

Sarnataro Daniela D Pepe Anna A Altamura Gennaro G De Simone Imma I Pesapane Ada A Nitsch Lucio L Montuori Nunzia N Lavecchia Antonio A Zurzolo Chiara C

Scientific reports 20160413

The 37/67 kDa laminin receptor (LR) is a non-integrin protein, which binds both laminin-1 of the extracellular matrix and prion proteins, that hold a central role in prion diseases. The 37/67 kDa LR has been identified as interactor for the prion protein (PrP(C)) and to be required for pathological PrP (PrP(Sc)) propagation in scrapie-infected neuronal cells, leading to the possibility that 37/67 kDa LR-PrP(C) interaction is related to the pathogenesis of prion diseases. A relationship between 3 ...[more]

PMID: 27071549

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Project description:Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. Hence, new anti-liver cancer treatment strategies need to be urgently developed. Coptisine is a natural alkaloid extracted from rhizoma coptidis which exhibits anticancer activity in various preclinical models, including liver cancer. However, the molecular mechanisms underlying the anti-liver cancer effects of coptisine remains unclear. We used flow cytometry to assess the binding of coptisine to 67LR expressed on the surface of SMMC7721, HepG2, LO2 and H9 cells. Then SMMC7721, HepG2 and BEL7402 cells, belonging to the HCC cell lines, were treated with coptisine. The cell viability was detected using a cell counting kit-8 assay. Apoptosis was evaluated using flow cytometry and transferase-mediated dUTP nick-end labeling (TUNEL) assay. Apoptotic-related proteins and tumor death receptor 67-kDa laminin receptor (67LR) were detected using Western blot analysis. The cyclic guanosine 3',5'-monophosphate (cGMP) concentration was determined using enzyme-linked immunosorbent assay. sh67LR lentivirus, anti67LR antibody, and cGMP inhibitor NS2028 were used to determine how a 67LR/cGMP signaling pathway regulated coptisine-induced apoptosis. Tumor growth inhibited by coptisine was confirmed in a SMMC7721 cell xenograft mouse model. Coptisine selectively exhibited cell viability in human hepatoma cells but not in normal human hepatocyte cell line LO2 cells. Coptisine promoted SMMC7721 and HepG2 cell apoptosis by increasing 67LR activity. Both 67LR antibody and sh67LR treatment blocked coptisine-induced apoptosis and inhibition of cell viability. Coptisine upregulated the expression of cGMP. Moreover, cGMP inhibitor NS2028 significantly decreased coptisine-induced apoptosis and inhibition of cell viability. In vivo experiments confirmed that coptisine could significantly suppress the tumor growth and induce apoptosis in SMMC7721 xenografts through a 67LR/cGMP pathway. Coptisine-mediated 67LR activation may be a new therapeutic strategy for treating hepatic malignancy.

Dataset Information

The 37/67 kDa laminin receptor (LR) inhibitor, NSC47924, affects 37/67 kDa LR cell surface localization and interaction with the cellular prion protein.

Publications

The 37/67 kDa laminin receptor (LR) inhibitor, NSC47924, affects 37/67 kDa LR cell surface localization and interaction with the cellular prion protein.

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