Current Signal Transduction Therapy - Volume 4, Issue 1, 2009

Evasion of apoptosis (programmed cell death) is a hallmark of pancreatic cancer, one of the leading causes of cancer deaths in the western world. Resistance to apoptosis can promote the multistep process of tumorigenesis, since tissue homeostasis is disturbed by too little cell death. Further, defects in apoptosis programs can leads to treatment failure in pancreatic cancer, since intact apoptosis pathways are critical to mediate therapy-induced cytotoxicity. Over the last decade, the exploration of apoptosis pathways and their dysregulation in pancreatic cancer has resulted in the identification of molecular targets that can be exploited for drug development and clinical application. Such apoptosis-based cancer therapeutics open new perspectives for rationally designed treatment strategies for patients with pancreatic cancer.

The dynamic cross-talk between bench-based research and clinical practice is the fundamental characteristic of modern oncology. Colorectal cancer, the second most common cause of cancer-related death in the Western world, is the paradigm of the revolutionary use of targeted sophisticated therapies. The continuous unraveling of the molecular identity of signaling pathways that govern sub-cellular decisions reveals candidate targets. The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signaling pathways are considered major tumor-promoting cascades. Three monoclonal antibodies have been approved for the management of metastatic colorectal cancer. Cetuximab and panitumumab target the EGFR-signaling pathway, inhibiting the aberrant transduction of tumor-proliferating signals, as well as promoting tumor cell apoptosis. Bevacizumab is the first antibody inhibiting VEGF-driven formation of new blood vessels, a critical component of tumor metastasis. Randomized clinical trials in patients with colorectal cancer have shown significant clinical benefit and tolerable toxicity with the use of these antibodies. At the era of clinical bioinformatics, better selection of patient subpopulations with tumor-over-expressing specific clinical biomarkers could result in significant enhancement of signal transduction targeting success. This review discusses characteristics of cancer-associated signaling, describes the mechanism of action of the three monoclonal antibodies, focusing on their current role in the management of colorectal cancer.

Leptin is a hormone whose central role is to regulate endocrine functions and to control energy expenditure. After the discovery that leptin can also have pro-inflammatory effects, several studies have tried to address - at the molecular level - the pathways involved in leptin-induced modulation of the immune functions in normal and pathologic conditions. The signaling events influenced by leptin after its binding to the leptin receptor have been under scrutiny in the past few years, and considerable experimental work has elucidated the consequences of leptin effects on immune cells. This review examines the biochemistry, function and regulation of leptin signaling in view of possible intervention on this molecule for a better management and therapy of immune-mediated diseases.

Hedgehog (Hh) proteins belong to a class of morphogens involved in many biological processes during embryonic development; they are relatively silent during normal adult life although they may be recruited postnatally in response to tissue injury. Three secreted proteins have been identified: Sonic hedgehog (Shh), Desert hedgehog and Indian hedgehog. The interaction of Hh ligand with its receptor Patched-1 triggers the activation of smoothened and initiates transduction events that lead to the regulation of transcriptional factors belonging to the Gli family. Hh pathway orchestrates both coronary development and adult coronary neovascularisation by controlling the expression of multiple proangiogenic genes and anti-apoptotic cytokines. Shh pathway enhances the recruitment of endothelial progenitor cells in addition to the mechanisms described for other Hh and concurs to its myocardial protection. In cerebral ischemia, Hh mimicking molecules has been reported to limit damages caused by vessel occlusion. Besides, Shh carried by microparticles corrects endothelial injury through nitric oxide release. Anomalous activations of Hh pathway are implicated in various types of tumours including medulloblastoma, carcinoma of esophagus, stomach, pancreas and colon. Hh can influence angiogenesis in both positive and negative manner and they may have implication for therapeutic strategies to treat either ischemic or cancer diseases.

Methionine oxidation by reactive oxygen species and reduction mediated by the methionine sulfoxide reductase (Msr) system may attenuate protein function in signal transduction pathways. This review will focus on two potential protein targets for methionine oxidation involved in signal transduction of the immune response: Ca2+/calmodulin-regulated phosphatase calcineurin (Cn) and inhibitor of kappa B-alpha (IkBα). The major known function of Cn is to regulate nuclear localization of the nuclear factor of activated T cells (NFAT), a family of transcription factors during immune stimulus. Like wise, IκBα inhibits the activity of nuclear factor kappa B (NFkB), which is known to regulate the transcription of various genes participating in immunological and oxidative stress response. Modification of Met 45 in IκBα enhances its resistance to protein-degredation; thereby, preventing NFkB from activating transcription in cells of the immune system. Similarly, the human Cn molecule contains several methionine residues that are either located next to a cysteine residue or a methionine residue. Accordingly, it is suggested that oxidation of a specific Cn-methionine may interfere with the proper NFAT nuclear-localization and transcriptional activation in T-cell. Thus, the roles of oxidized-methionine residues and their reduction, by the Msr system, are discussed as potential regulators of cellular immune response.

Cancer is a genetic disease which progresses from benign to malignant stages through the steady acquisition of genomic mutations in key cell-regulatory genes, namely oncogenes, tumor-suppressors, and stability genes. In many ways cancer is considered as a disease of de-regulated signal transduction. Oncogenic mutations frequently lead to overexpression and/or constitutive activation of signal transduction components, allowing cancer cells to override the controlling mechanisms of signalling networks and acquire the cancer-associated traits known as the six hallmarks of cancer. The molecular chaperone HSP90 is viewed as a key player in the subversion of normal cells toward transformation, since many of its client proteins are linked to signalling pathways, commonly de-regulated during tumorigenesis. Consequently, over the past years HSP90 has emerged as a promising and exciting target for the development of cancer chemotherapeutics and already several HSP90 inhibitors are under clinical evaluation. Recently, a pool of HSP90 was identified at the cell surface, where it was shown to be involved in signalling pathways leading to cell motility and invasion. Independent studies suggest that surface HSP90 could be a promising target for the development of effective anti-metastatic strategies. Thus a need for the development of novel cell-impermeable HSP90 inhibitors is emerging.

Cell movement and adhesion serve critical roles in a wide variety of physiological situations, and when dysregulated can contribute to the pathogenesis of many diseases. Recently, Lyn kinase has emerged as a crucial regulator of ‘inside-out’ integrin signaling in hematopoietic cells, that when dysregulated, can lead to the development of an “invasive cell” phenotype in a variety of pathological contexts ranging from leukemia to neuro-inflammatory disorders. Here, we discuss several pathologies associated with perturbations of Lyn-dependent inside-out integrin signaling pathways in blood cells.

Cyclooxygenase (COX) and nitric oxide synthase (NOS) are two isoenzyme families that both implicated in the inflammatory process. Indeed, the activities of both enzymes are so important that two of the most important classic drugs, Aspirin and Nitroglycerin, are directly related to the COX pathway and NO pathway, respectively. Although Aspirin has been used as an anti-inflammatory drug since 1876, it was not until 1970s that its action has been shown to be involved in inhibition of the Cox enzyme, being a class of drugs known as non-steroidal anti-inflammatory drugs(NSAIDs). This signaling pathway has led to extensive research led by a number of pharmaceutical companies in the race to make more effective anti-inflammatory drugs, such as ibuprofen and colecoxib to name but a few. Similarly, the nitroglycerin has been used to treat angina more than a hundred years, it's only until late 1980s its drug action by releasing nitric oxide gas have been recognized. There are not however, many anti-inflammatory drugs that specially target NOS or more specifically, iNOS, although there are various studies and trial that are investigating the effect of iNOS inhibition in various inflammatory conditions such as sepsis and other chronic illness including cancer. More recently, COX pathway has been found to be regulated by NO pathway and therapeutic potentials of NO-releasing aspirin hybrid drugs has been developed. In this review, we will discuss both pathways and their cross talk and pharmaceutical potentials for future therapeutic development based on these signaling transduction pathways.