Current Signal Transduction Therapy - Volume 4, Issue 3, 2009

Cancer invasion and metastases are the hallmarks of malignant tumors and the cause of most cancer deaths. Molecular alterations that arise during cancer progression and that generate abnormal gene products, activated signal transduction pathways, and altered cancer cell-host stroma interactions can be considered targets of therapeutic drugs. Some of these drugs have already entered clinical trials, while others have shown promising results. In this review, we examine some of the successive steps of the metastatic process: cancer cell migration and invasion of the tumor microenvironment, angiogenesis and following extravasation focusing on the deranged signalling pathways underlying the malignant phenotypes. Finally, the application of new proteomic methodologies to detect cancer earlier and for a patienttailored therapy is illustrated.

Cerebral ischemia is the third leading cause of death in industrialized countries and an important health system problem with no efficient treatment to date. The reduction in oxygen and glucose supply triggers a cascade of events such as excitotoxicity, oxidative stress, inflammation, apoptosis, and an adjustment of the gene expression program. The hypoxia inducible factor-1 (HIF-1) is a transcription factor that mediates the adaptive responses to the reduction in oxygen availability. HIF-1 activation in hypoxic conditions promotes the survival of cells through the induction of adaptive genes involved in glucose and energy production, glucose transport, cell proliferation, cell survival, iron homeostasis, erythropoiesis, angiogenesis and vascular reactivity. In recent years, biomedical research has focused on the oxygen regulated α subunit of HIF-1 as a potential therapy in medical events that involve hypoxic conditions. In this review we summarize current knowledge on the use of HIF-1α as a therapeutic target against cerebral ischemia through two different strategies: 1) the use of ischemic preconditioning to induce the HIF-1 pathway regulation, and 2) the pharmacological inhibition of prolyl and asparaginyl hydroxylases. Both strategies appear as attractive options for protection in ischemia in which signaling pathway activation could contribute to the establishment of tolerance in brain.

Bone Morphogenetic Proteins (BMPs), members of the TGF-β superfamily, are pleiotropic growth factors, known for their role in embryogenesis and bone induction. BMPs signal via two types of serine/threonine kinase BMP receptors (BMPRs), type I, and type II receptors. Ligand binding induces activation of the downstream signalling molecules, the SMADs, which regulate the expression of BMP-responsive genes including those involved in processes such as differentiation, proliferation and apoptosis. BMP signalling is coordinated by both extrinsic and intrinsic mechanisms in order to ensure the control of these important processes. Irregularities however, can occur at any step during the downstream BMP pathway, and aberrations have been implicated in the pathogenesis of several tumour types including: prostate, colorectal, osteosarcomas, myelomas and breast cancer, amongst others. As so many signalling molecules take part in the BMP network, the specific role that these characters play in the pathogenesis of these tumours is rather complex, and hence unclear. In this review, we summarise and consider current literature on BMP signalling, its regulation, and any aberrations in the pathway, focusing on the role of BMPRs, and SMADs on the development, progression and metastasis of solid tumours.

Since recognition of HIV, many scientists in several branches have attempted to inactive it. Although different methods are available to destroy it, but these methods may damage vital cells too. This paper suggests a theoretical method to paralyze only HIV. The virus contains certain glycoprotein (gp120) which permits HIV to attach receptor host cell (CD4). Applying a sinusoidal electric field with a definite frequency makes gp120 to oscillate. This periodic electric field is superposed with another electromagnetic signal with plasma frequency to shock gp120 and causes separation of gp120 from HIV, consequently causes Paralysation of HIV.

In immune-mediated chronic inflammation the balance between pro-inflammatory and anti-inflammatory cytokines is skewed so that elevated levels of circulating pro-inflammatory cytokines of the interleukin (IL), interferon (IFN) protein families and TNF-α is favored. Several of the pro-inflammatory IL-family cytokines, including most prominently, IL-6, IL-12, IL-17, IL-23, as well as IFN-γ, activate the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway where phosphorylated (i.e. activated) STAT proteins become potent transcription factors for specific STAT-target genes. Moreover, ‘cross-talk’ between JAK/STAT signaling, SAP/MAPK and the phosphatidyl inositide-3-kinase (PI3K) pathway has been demonstrated. Thus, activation of the SAP/MAPK and PI3K pathways by JAK/STAT can initiate pleiotypic cellular responses that regulate cellular proliferation, survival, development and apoptosis. Further, inflammatory responses typically seen in rheumatoid arthritis, irritable bowel disease, chronic heart failure and diseases of the eye appear to accelerate when the JAK/STAT pathway itself becomes dysregulated. Of note, the outcomes of several human clinical trials demonstrated efficacy in reducing some objective markers of chronic inflammation by inhibiting IL-6-mediated signaling. In addition, evidence from one of these trials showed that suppression of IL-6 signaling also dampened STAT phosphorylation. This result suggested that the targeting of JAK/STAT signaling with small molecule inhibitors may also suppress chronic inflammatory responses.

The immunosuppressive drugs Cyclosporine A (CSA) and prednisolone are widely used to prevent graftversus- host-disease (GVHD) after allogenetic stem cell transplantation (allo-SCT). However, it remains to be elucidated whether these drugs have an effect on the balance of effector cells and CD4+CD25+ regulatory T cells (Tregs) which determines the development of stable allograft tolerance. In the current study, we found that proliferation, activation and function of T cells especially for virus-specific CD8+ T cells and Tregs were inhibited by CSA and prednisolone in a dosedependent manner. These effects were associated with lower secretion of cytokines and arresting T cells in the G0/G1 phase of cell cycle. Moreover, CSA and prednisolone could reduce the expression of FOXP3 and suppressive function of Tregs. Our data indicated that CSA and prednisolone impaired the development and function of CD8+ T cells as well as Tregs in a similar way suggesting that CSA and prednisolone might increase the susceptibility to develop viral diseases and block the potential induction of immune tolerance in clinical settings.