Phosphodiesterase function and endocrine cells: links to human disease and roles in tumor development and treatment.

Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate, and, consequently, exhibit a central role in multiple cellular functions. The pharmacological exploitation of the ability of PDEs to regulate specific pathways has led to the discovery of drugs with selective action against specific PDE isoforms. Considerable attention has been given to the development of selective PDE inhibitors, especially after the therapeutic success of PDE5 inhibitors in the treatment of erectile dysfunction. Several associations between PDE genes and genetic diseases have been described, and more recently PDE11A and PDE8B have been implicated in predisposition to tumor formation. This review focuses on the possible function of PDEs in a variety of tumors, primarily in endocrine glands, both in tumor predisposition and as potential therapeutic targets.

Expression of the xenobiotic- and reactive oxygen species-detoxifying enzymes, GST-pi, Cu/Zn-SOD, and Mn-SOD in the endocrine cells of colorectal cancer.

BACKGROUND AND AIM: The aim of the present work was to analyze the expression of antioxidant enzymes GST-pi, SOD1, and SOD2 in endocrine cells of colorectal cancers and to evaluate the significance of the presence of thus labeled endocrine cells as prognostic factor. METHODS: The expression of chromogranin A (ChGA), GST-pi, SOD1, and SOD2 was determined in endocrine cells of 128 colorectal cancers using light and electron immunohistochemistry and double immunogold labeling method. RESULTS: Endocrine cells expressing at least one of the studied antioxidant enzymes were detected in a relatively small proportion of primary colorectal cancers (22 cases, 17%; 14% GST-pi-positive, 14% SOD1-positive, and 9% SOD2-positive). The double immunogold staining and the following electron microscopy showed that GST-pi, SOD1, and SOD2 were co-localized with ChGA to the granules of most endocrine cells. The survival analyses revealed that patients with endocrine cells in primary tumor tissues expressing GST-pi had worse prognosis after the surgical therapy than those without GST-pi-positive endocrine cells (median of 22.70 vs. 49.43 months, p < 0.05, Log-rank test). CONCLUSIONS: Most of the ChGA-positive endocrine cells in colorectal cancers also expressed some or all of the three studied antioxidant enzymes, GST-pi, SOD1, and SOD2. Moreover, patients having tumors with GST-pi-positive endocrine cells have an unfavorable prognosis. We suggest that not the neuroendocrine differentiation in general, but the presence in the tumors of endocrine cells with activated antioxidant defense and probably metabolically more active might determine a more aggressive type of cancer leading to worse prognosis for patients.

Expression of H(+),K(+)-ATPase and glycopattern analysis in the gastric glands of Rana esculenta.

A multidisciplinary study involving lectin histochemistry, IHC, immuno-lectin blotting, and immunogold was carried out to determine the distribution of sugar residues in the glycoproteins of Rana esculenta oxynticopeptic cells. We considered animals in two experimental conditions, fasting and fed. It is known that, in mammals, the tubulovesicular membranes are rich in proteins with several functions. The proton pump H(+),K(+)-ATPase, a heterodimeric complex with a catalytic alpha-subunit and a heavily glycosylated beta-subunit, responsible for acid secretion, is the most abundant. No data have been published regarding the localization and the structures of H(+),K(+)-ATPase in amphibians. In the water frog, the luminal membrane and tubulovesicular system of oxynticopeptic cells, which differ in morphology according to their functional stage, reacted with the primary gold-conjugated antibody against the H(+),K(+)-ATPase alpha-subunit. By lectin histochemistry and immunoblotting, in the oxynticopeptic cells of R. esculenta we detected the presence of N-linked glycans having fucosylated (poly)lactosamine chains, which could correspond to the oligosaccharide chains of the beta subunit. The latter are somewhat different from those described in mammals, and this is probably because of an adaptation to the different microenvironmental conditions in which the oxynticopeptic cells find themselves, in terms of their different habits and phylogeny.