Ricerc@Sapienza

Chronic inflammation has been associated to cancer development by the alteration of several inflammatory pathways, such as Nuclear Factor-kappaB pathway. In particular, IkappaB kinase alpha (IKKalpha), one of two catalytic subunits of IKK complex, has been described to be associated to cancer progression and metastasis in a number of cancers. The molecular mechanism by which IKKalpha affects cancer progression is not yet completely clarified, anyway an association between IKKalpha and the expression of Maspin (Mammary Serine Protease Inhibitor or SerpinB5), a tumor suppressor protein, has been described. IKKalpha shuttles between cytoplasm and nucleus, and when is localized into the nuclei, IKKalpha regulates the expression of several genes, among them Maspin gene, whose expression is repressed by high amount of nuclear IKKalpha. In prostate cancer, high levels of Maspin have been associated with reduced metastatic progression and the expression of Maspin avoids the transformation process into a generation of stem-like cells, leading instead to a more epithelial phenotype. The project aims to demonstrate that the repression of IKKalpha nuclear translocation could be associated with the repression of metastatic phenotype through the ability of a glucosamine derivative, 2-(N-Carbobenzyloxy)-L-phenylalanylamido-2-deoxy-ß-d-glucose (NCPA), synthesized in our laboratory, to stimulate the production of Maspin in hormone-responsive (LNCaP) and hormone-refractory (PC3) prostate cancer cell lines. Moreover, since our molecule is a glucosamine analog, the study would like to demonstrate if NCPA could interfere with N-acetylglucosilation processes, increased in cancer cells where metabolic reprogramming involves a passage in energy production by oxidative phosphorylation to a less efficient glycolysis even in the presence of high oxygen stresses