Thrombospondin-1 (TSP-1) was first isolated from platelets that had been stimulated with thrombin and so was designated 'thrombin-sensitive protein'. Since its first recognition, TSP-1 has been found to participate in multiple biological processes including angiogenesis, apoptosis, activation of TGF-beta, and immune regulation. As such, TSP-1 is designated a multifunctional protein. TSP-1 has multiple receptors, among which CD36, CD47, and integrins are of particular note. TSP-1 is an antiangiogenic, inhibiting the proliferation and migration of endothelial cells by interactions with CD36 expressed on their surface of these cells. Inhibitory peptides and fragments of TSP1 bind to CD36, leading to the expression of FAS ligand (FasL), which activates its specific receptor Fas. This leads to the activation of caspases and apoptosis of the cell. Since tumors overexpressing TSP-1 typically grow slower, exhibit less angiogenesis, and have fewer metastases, TSP1 is an attractive target for cancer treatment. Because TSP1 is extremely large (~120 kDa monomer), not very abundant, and exerts multiple actions, its clinical usefulness is questionable. However, small-molecules based on a CD36-binding peptide sequence from TSP1 are being tested. One analog, ABT-510, exhibits potent proapoptotic activity in cultured cells, while clinically it is very well tolerated with therapeutic benefits reported against several malignancies. ABT-510 is being evaluated in clinical trials for the treatment of several types of cancer.
Swiss-Prot Accession Number: P07996