Juliana Felgueiras

Prostate cancer: the need for biomarkers and new therapeutic targets.

Prostate cancer (PCa) incidence and mortality have decreased in recent years. Nonetheless, it remains one of the most prevalent cancers in men, being a disquieting cause of men’s death worldwide. Changes in many cell signaling pathways have a predominant role in the onset, development, and progression of the disease. These include prominent pathways involved in the growth, apoptosis, and angiogenesis of the normal prostate gland, such as androgen and estrogen signaling, and other growth factor signaling pathways. Understanding the foundations of PCa is leading to the discovery of key molecules that could be used to improve patient management. The ideal scenario would be to have a panel of molecules, preferably detectable in body fluids, that are specific and sensitive biomarkers for PCa. In the early stages, androgen deprivation is the gold standard therapy. However, as the cancer progresses, it eventually becomes independent of androgens, and hormonal therapy fails. For this reason, androgen-independent PCa is still a major therapeutic challenge. By disrupting specific protein interactions or manipulating the expression of some key molecules, it might be possible to regulate tumor growth and metastasis formation, avoiding the systemic side effects of current therapies. Clinical trials are already underway to assess the efficacy of molecules specially designed to target key proteins or protein interactions. In this review, we address that recent progress made towards understanding PCa development and the molecular pathways underlying this pathology. We also discuss relevant molecular markers for the management of PCa and new therapeutic challenges.

The power of the yeast two-hybrid system in the identification of novel drug targets: building and modulating PPP1 interactomes

Since the description of the yeast two-hybrid (Y2H) method, it has become more and more evident that it is the most commonly used method to identify protein–protein interactions (PPIs). The improvements in the original Y2H methodology in parallel with the idea that PPIs are promising drug targets, offer an excellent opportunity to apply the principles of this molecular biology technique to the pharmaceutical field. Additionally, the theoretical developments in the networks field make PPI networks very useful frameworks that facilitate many discoveries in biomedicine. This review highlights the relevance of Y2H in the determination of PPIs, specifically phosphoprotein phosphatase 1 interactions, and its possible outcomes in pharmaceutical research.

Signaling pathways in anchoring junctions of epithelial cells: cell-to-cell and cell-to-extracellular matrix interactions.

Abstract Epithelial cells form the epithelium, one of the basic tissues of the human body. These cells present specializations from tissue to tissue, determining different structures and functions. Tissues formed by epithelial cells are characterized by the few extracellular matrix found between adjacent cells. In this way, to preserve tissue integrity, cells have to stick to each other and have to maintain a strict communication with the environment via cell junctions. Signal transduction is the main way of cell communication, being vital for the regulation of cell survival and proliferation. In cell junctions, this communication occurs through cell adhesion molecules that promote cell-to-cell and cell-to-extracellular matrix adhesion, as well as, enable the flow of information to the inside and to the outside of the cell. These molecules include integrins and cadherins, among others. The impairment of cell signaling in epithelial junctions has been involved in several pathological processes that underlie the development of, for example, colorectal cancer. Thus, epithelial cell signaling mediators have been explored as potential therapeutic targets and efforts have been made to achieve a deeper understanding of molecular events that occur at cell junctions. In this review, we address the current knowledge on the main signaling events that take place in anchoring junctions of epithelial cells, focusing both on cell-to-cell and cell-to-matrix interactions. To conclude, we explore some relevant consequences from epithelial cell signaling impairment and demonstrate that the molecular mediators of the pathways analyzed may be putative therapeutic targets.

TGF-β cascade regulation by PPP1 and its interactors –impact on prostate cancer development and therapy

Protein phosphorylation is a key mechanism by which normal and cancer cells regulate their main transduction pathways. Protein kinases and phosphatases are precisely orchestrated to achieve the (de)phosphorylation of candidate proteins. Indeed, cellular health is dependent on the fine‐tune of phosphorylation systems, which when deregulated lead to cancer. Transforming growth factor beta (TGF‐β) pathway involvement in the genesis of prostate cancer has long been established. Many of its members were shown to be hypo‐ or hyperphosphorylated during the process of malignancy. A major phosphatase that is responsible for the vast majority of the serine/threonine dephosphorylation is the phosphoprotein phosphatase 1 (PPP1). PPP1 has been associated with the dephosphorylation of several proteins involved in the TGF‐β cascade. This review will discuss the role of PPP1 in the regulation of several TGF‐β signalling members and how the subversion of this pathway is related to prostate cancer development. Furthermore, current challenges on the protein phosphatases field as new targets to cancer therapy will be addressed.

A ruthenium(II)-trithiacyclononane curcuminate complex: Synthesis, characterization, DNA-interaction and cytotoxic activity

Abstract The coordination of ruthenium(II) complexes to anionic oxygen-based donors are very rare. This study describes a simple, one-pot method for obtaining [ruthenium(II)(trithiacyclononane)(curcumin)(S-DMSO)]Cl (1) in 37% yield. The structural characterization of complex 1 by elemental analysis, FT-IR, 1-D and 2-D NMR, ESI+-MS as well as UV–vis and fluorescence spectroscopies are presented. The DNA-melting temperature (Tm) assay shows that salmon sperm DNA (smDNA) in the presence of complex 1 has a higher melting temperature, with ΔTm = 7.4 °C, while in the presence of curcumin the melting temperature remains unaltered. The in vitro cytotoxic activities of curcumin and complex 1 were investigated using the tumor human prostate cell line, PC-3, and the healthy cell line, PNT-2. Complex 1 is innocuous toward normal prostate epithelial cells and, whereas curcumin is toxic, with inhibition rates of ca. 35 and 65% at 50 and 80 μM, respectively. On the tumor cell line PC-3, complex 1 did not cause viability changes, whereas curcumin exhibited dose-dependent inhibition, with ca. 73% inhibition at the highest concentration tested, i.e. 80 μM. This study suggests that coordination with the trithiacyclononane ruthenium(II) scaffold stabilizes the photochemical properties of curcumin and strongly changes its biologic activity.