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
Litvinov et al. reports that androgenic ablation therapy is not curative because it leads to the accumulation of molecular changes that induce increased functions and new signal pathways triggered by AR without the binding to androgenic ligand. The current screening method for prostate cancer is based on the measurement of specific prostate antigen (PSA) and on a digito-rectal test (DRE), but the final diagnosis is based on the results of an ultrasound trans-rectal biopsy (PBs). The introduction of the PSA test in the late 1980s has led to an increase in the discovery of new PCA cases. However, the PSA has some well-known limitations; it lacks a diagnosis of specificity and prognostic value and also leads to the detection of a high percentage of false positives. This lack of specificity is associated with a percentage increase in PB negative and overdiagnosis of many indolent tumors and consequent overtreatment of patients. As a result, there is an urgent need to find a more effective and specific PCA marker.
Several data reported in literature, associate the absence of Maspin to cancer progression. Therefore, Maspin expression, better correlated with prognosis, may serve as a biomarker for prostate cancer cells responding to androgenic ablation therapy (Zou Z.et al, Clin Cancer Res 2002).
Therefore, studies focused on the stimulation of Maspin production, both in hormone-sensitive and -insensitive cell lines would be interesting to find new diagnostic markers. Maspin controls the expression of several molecules, with different roles in the cells, for this reason to find new molecules that are under the control of Maspin, could give the opportunity to find new markers.
Moreover, to study molecules able to induce the endogenous production of Maspin, which has been described as a tumor suppressor protein involved in tumor progression and metastasis, would be interesting to find new strategies to treat prostate cancers.
Considering that presence or absence of Maspin has been described as representative of early and late stages of several types of cancer, and considering that PC3 (hormone-insensitive) and LNCaP (hormone-sensitive) are representative of late and early cancer stage, respectively, to study the stimulation of Maspin in these two different cell lines could give the opportunity to understand how to treat cancers at different progression stages.