Current Signal Transduction Therapy - Volume 1, Issue 2, 2006

Based on recent research neuroinflammation is more than just a pathological mechanism in neurodegenerative diseases. As representatives for the cytokine family we will review the functions of Interleukin-6 and Tumor Necorosis Factor with respect to their role in neuroprotection and neurodegeneration. Both cytokines have been found to be strongly upregulated during diseases such as Alzheimer's disease, stroke or Parkinson's syndrome. By comparing signaling function of these cytokines during health and disease it becomes clear that the role of cytokine mediated tissue modulation depends very much on the molecular and cellular state of nerve cells e.g. physiological vs. pathological. Finally, we will discuss the possibilities of using cytokine activated pathways as a potential targets for therapeutic avenues.

The identification of the causes of cancer at the cellular level has led to the discovery of the Epidermal Growth Factor Receptor (EGFR)/Ras/Mitogen-Activated Protein Kinase (MAPK) signaling pathway as a target for the development of anti-cancer strategies. A variety of therapeutic approaches to inhibit the EGFR/Ras/MAP module are currently being tested in clinical trials or have even been approved for the treatment of some tumors. However, more efficient ways to block the EGFR/Ras/MAPK pathway in tumor cells still have to be developed. The subcellular localisation of each member of this module is of pertinent importance to ensure signaling. Accumulating evidence suggests that targeting/scaffold proteins regulate the assembly, localization and activity of EGFR/Ras/MAPK signal transduction components. In particular proteins that stimulate the lysosomal downregulation of the EGFR and the targeting of Ras regulators/effectors to Ras could contribute to improve strategies to inhibit EGFR/Ras signaling in cancer. These proteins include the Cbl/CIN85/endophilin pathway, caveolin, galectins, annexins, Impedes Mitogenic Signal Propagation (IMP), 14-3-3 and Kinase Suppressor of Ras (KSR). Here we will review the current literature regarding the potential of targeting/scaffold proteins to affect the lysosomal targeting of EGFR and the subcellular localization of the Ras/MAPK signaling cascade.

Mechanical ventilation can be lifesaving, but may initiate and perpetuate ventilator-induced lung injury. This has many manifestations, from pneumothorax to multi-system organ failure. Although the precise underlying mechanisms have not yet been elucidated, various signalling pathways are thought to be involved and shall be discussed in this review. A key component in the pathogenesis of lung injury is 'biotrauma', comprising a triggering of intracellular signalling pathways to upregulate inflammatory processes in response to alveolar membrane deformation. This mechanotransduction arises from a possible combination of at least three mechanisms: Activation of stretch-sensitive alveolar membrane ion channels, plasma membrane disruption causing a wave of calcium release and/or integrin activation producing cytoskeletal rearrangement. The consequence is increased expression of c-fos and Nuclear Factor-κB, important regulators of the inflammatory response. Since an understanding of the signalling cascades involved will help to design strategies to diminish the immune response, this review also highlights the implications for therapies to minimise lung damage in the clinical setting, such as the use of anti-TNF-α -antibody. There is obviously much scope for future research in this area, and perhaps further investigation into components of the cascades will reveal potential targets for therapeutic interventions? In this way, the mortality of ventilated patients may be reduced.

Apoptosis, the cell's intrinsic death program, is a key regulator of tissue homeostasis. Thus, any imbalance between cell death and proliferation may favor tumor formation. Moreover, killing of cancer cells by cytotoxic therapies currently used in clinical oncology such as chemotherapy or γ-irradiation is primarily mediated by triggering apoptosis as well as other forms of cell death in cancer cells. Accordingly, defects in apoptosis pathways may lead to cancer resistance. Understanding the molecular pathways that regulate apoptosis in different types of malignancies and how resistant cancer cells successfully evade to undergo apoptosis may provide novel opportunities for cancer drug development. Thus, apoptosis pathways may be exploited for cancer treatment by directly triggering cell death in tumor cells, e.g. via ligation of death receptors, or by enhancing the efficacy of conventional cancer therapies, e.g. by blockade of anti-apoptotic programs. In this review we will focus on the potential exploitation of the death receptor pathway, in particular TRAIL, for cancer therapy. Also, we will discuss signal transduction therapy targeting Inhibitor of Apoptosis Proteins (IAPs).

T-cell zeta chain expression, phosphorylation and degradation and their role in T-cell signal transduction and immune response regulation in health and disease. Zeta chain is a stable constituent of the antigen specific T-cell receptor and its phosphorylation is one of the earliest and key events in the T-cell signal transduction. Zeta chain phosphorylation is strictly controlled by the action of sarcomafamily kinases and also by phosphatases, indicating its crucial role in antigen specific T-cell activation. Furthermore, after its phosphorylation and T-cell activation, ζ-chain is ubiquitylated and degraded, a fact suggesting that its level on T-cell surface is also under control and contribute to the regulation of an initiated immune response. Zeta chain expression and/or phosphorylation seems to be of great importance in many clinical conditions from the pathogenesis of various types of cancer to the immunosuppressive state in dialysis patients. Its levels are also affected by chronic inflammation. In addition to its role in the antigen specific signal transduction, ζ-chain is present only in T-cells and natural killer cells, making it a possible target for immunotherapeutic applications. The recent discovery of specific inhibitors of ζ-chain phosphorylation opens new horizons for future research and for possible therapeutic interventions in various clinical conditions.

Erythropoietin (Epo) plays an essential role in the regulation of erythropoiesis by stimulating growth, preventing apoptosis, and promoting terminal differentiation of erythroid progenitors. The Epo receptor belongs to the cytokine receptor superfamily. Epo and its receptor have been localized to several nonhematopoietic tissues and cells, including the central and peripheral nervous systems, endothelial cells and heart. Epo exerts neuronal, vascular and cardiac protection through multiple signaling pathways in different models of tissue and cell injury in vitro and in vivo, such as ischemia, hypoxia, inflammation and oxidative stress. As a result, Epo has been suggested as a possible candidate in the treatment of neurological and cardiac disorders. A better understanding of cellular pathways and molecules modulated by Epo signaling is crucial in determining the potential therapeutic application of recombinant human Epo and may provide further insights in the development of both better synergistic therapies as well as new molecular targets. In this review, we summarize the current knowledge on the signaling pathways by which Epo offers neuroprotection and cytoprotection, signal transduction systems modulated by Epo and negative regulation of Epo signaling in the nervous system.

Androgen-independent (AI) progression remains the main obstacle to improving the survival of patients with prostate cancer. Recently, we characterized changes in gene expression profile during AI progression in the prostate cancer model systems as well as the clinical specimens, and identified several genes, including bcl-2, bcl-xL, clusterin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-5 and heat shock protein 27, that are involved in the signal transduction pathways mediating resistance to various kinds of apoptotic stimuli. We then showed the efficacy of inactivating such antiapoptotic genes using antisense (AS) oligodeoxynucleotides (ODNs) to delay AI progression after androgen withdrawal. We further demonstrated the synergistic effects of AS ODN therapy combined with several treatments, such as cytotoxic chemotherapy, radiation and other molecular targeting therapies. In this review, we attempted to summarize the progress we have made in the field of AS ODN strategy against prostate cancer, and to discuss the preliminary data of the recently completed phase I clinical trials using AS ODNs as well as the future prospects of this therapy. The findings presented in this review may help clarify the significance of AS ODN therapy targeting relevant genes as an attractive alternative to conventional strategies for prostate cancer.

For many years the mechanisms of intrinsic or acquired drug resistance have been the major object for molecular oncologists and clinicians, because resistance to chemotherapy critically limits the outcome of cancer treatment. Initially, the interaction of a drug with its molecular target that yields a lethal lesion has been studied - at the target level or upstream of this interaction (drug influx and efflux, detoxification, DNA repair etc.). Later, it was discovered that downstream cellular responses to a given DNA lesion can determine the outcome of the therapy, focusing the investigation on the processes of the programmed cell death. More recently a new phenomenon of drug resistance has been discovered, called Cell Adhesion-Mediated Drug Resistance. It is based on the adherence of cells to extracellular matrix proteins through adhesive molecules such as integrins. Integrins are cell surface heterodimeric receptors that mediate cell-extracellular matrix adhesion. They trigger many intracellular signaling pathways involved in a cell proliferation, survival/apoptosis, shape, polarity, motility, and differentiation. Integrins may protect cancer cells from an array of cytotoxic agents in several ways. This review will focus on the role of integrins in conferring resistance to tumor cells. We will discuss specific signal transduction pathways initiated by integrin ligation as a source of potential therapeutic targets for the fight against cancer.