Maspin functions to inhibit the urokinase plasminogen activator bound to its receptor, which decreases plasminogen activation, mediates internalization, and sensitizes cells to apoptosis. The prostate carcinoma (PC) model will be utilized as it can incorporate several themes of cancer progression and is the most diagnosed malignancy among American men with no successful treatment after metastasis. Evidence shows that maspin can inhibit PC invasion, and may be powerful anti-cancer therapy. When PC metastasizes to the bone, the osteoblasts begin to secrete high levels of TGF-beta, which increases the level of MMP 2 and 9. Maspin may inhibit the signaling cascade that leads to protease expression. The central hypothesis is that extracellular and intracellular maspin concertedly regulates the response of key factors in the tumor microenvironment and blocks excessive expression of ECM degrading enzymes.
Three specific aims are proposed: 1) to investigate the role of maspin on the expression of molecules involved in ECM remodeling,2) to examine the effect maspin has in the proteolytic activation of proteases involved in ECM remodeling, and 3) to investigate the contribution of intracellular maspin in proteolytic regulation.
| Yin, Shuping; Lockett, Jaron; Meng, Yonghong et al. (2006) Maspin retards cell detachment via a novel interaction with the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system. Cancer Res 66:4173-81 |
