Inside the function of the 67 kDa laminin receptor (67LR): a new promising target for cancer drug discovery by structure-based virtual screening
Pesapane, Ada (2010) Inside the function of the 67 kDa laminin receptor (67LR): a new promising target for cancer drug discovery by structure-based virtual screening. [Tesi di dottorato] (Inedito)
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The 67 kDa laminin receptor (67LR) is a non-integrin cell-surface receptor for the extracellular matrix derived from the dimerization of a 37 kDa cytosolic precursor (37LRP). 67LR is highly expressed in human cancers and widely recognized as a molecular marker of metastatic aggressiveness. Phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) is an anti-apoptotic protein whose expression is increased in several human cancers. In addition to apoptosis, PED/PEA-15 is involved in the regulation of other major cellular functions, including cell adhesion, migration, proliferation and glucose metabolism. A yeast two-hybrid screening identified 67LR as a PED/PEA-15 interacting partner. PED/PEA-15 molecular interaction with 67LR was confirmed by pull-down experiments on lysates of PED/PEA-15 transfected HEK-293 cells. Overexpressed and endogenous PED/PEA-15 co-immunoprecipitated with 67LR in PED/PEA-15 transfected HEK-293 cells and in U-373 glioblastoma cells, respectively. PED/PEA-15 overexpression significantly increased 67LR-mediated HEK-293 cell adhesion and migration to laminin that, in turn, determined PED/PEA-15 phosphorylation both in Ser-104 and Ser-116, through CamKII and PKC activation, thus enabling cell proliferation and resistance to apoptosis. Therefore, 67LR binding to laminin induces, through interaction with PED/PEA-15, signals that may be crucial for tumor cell survival in a poor microenvironment. Indeed, high 67LR expression predicts for a more aggressive disease in several types of cancer. These considerations prompted us to search for small molecules that might target 67LR activities. Since cancer cells overexpress 67LR, these compounds are expected to be cancer cell specific and minimally toxic. We conducted a computational screening of a diversity library of small molecules using the recently solved 67LR crystal structure, focusing on residues showed to be important for laminin binding. This analysis identified a lead compound that was characterized for its effects. This lead compound, NSC47924, could be the basis for the development of a new class of anti-cancer drugs, specifically targeting tumor invasion and metastasis.
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