Current Signal Transduction Therapy - Volume 7, Issue 3, 2012

Signal transducer and activator of transcription (STAT) proteins are second messengers in the JAK/STAT signaling pathway. The activation mechanism of STAT proteins involves phosphorylation on a single tyrosine residue by Janus-activated family kinases (JAK) in response to the binding of a series of extracellular proteins, such as cytokines, growth factors, hormones and membrane receptors. Activated via phosphorylation, STATs dissociate from the receptor, undergo dimerization and translocate to the nucleus, where they induce the transcription of target genes, commonly referred to as Interferon stimulated genes (ISGs). The family of STAT proteins has been documented to participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis and angiogenesis. Constitutively activated STATs are involved in an aberrant signaling pathway which has transforming properties and occurs in cancer development. This review describes the mechanisms of JAK/STAT activation in normal and cancer cells. Moreover, it outlines the role of the JAK/STAT pathway in the inflammatory process as well as in oncogenesis. Additionally, the contribution of STAT and JAK proteins in molecular targeted cancer therapy is discussed.

The effects of hydrogen peroxide, an oxidative agent, on the growth of A431 (an epidermoid carcinoma) cell line were investigated. It was also explored that whether or not the cell localization (peripheral or central position in a cell population) would modify the cell death-inducing effect of hydrogen peroxide. Anti-growth effect of hydrogen peroxide (0.05-1mM) on cell survival was tested by the MTT viability assay while the effect of it on DNA synthesis was measured by [3H] thymidine incorporation assay. Cell death mode (apoptosis or necrosis) was morphologically determined by double (Hoechst dye 33342/propidium iodide) staining. Effect of hydrogen peroxide on the mitotic figures was visualized by the hematoxylin staining. F-actin fibers were stained by using fluorescein isothiocyanate (FITC)-labeled phalloidine to present the effect of hydrogen peroxide on cell cytoskeleton. It was found that hydrogen peroxide showed anti-growth effects on cells in a dose-dependent manner. It inhibited the rate of DNA synthesis at relatively lower doses (100-400μM), while it induced apoptosis (400-600μM) and necrosis (600- 1000μM) at relatively higher doses. Interestingly, the cells located at the periphery of cell population were particularly vulnerable to cell death-inducing effect of hydrogen peroxide while those at the center remained relatively unharmed. This effect was confirmed by the visualization of damaged F-actin fibers of these peripherally located cells. Hydrogen peroxide shows a cytostatic effect at relatively lower concentrations, but it is cytotoxic at higher concentrations. In addition, peripherally located cells are much more sensitive to cell death-inducing effect of hydrogen peroxide.

Bladder cancer is the second most common malignancy of urinary tract. Normal bladder urothelium is a transitional epithelium which consist of 3-7 layers and three different types of cells. The question is what kind of cells is responsible for bladder cancer development, probably stem cells? Stem cells can be sensitive to changes in their environment including toxic substances related to smoking. These changes within stem cells may potentially induce carcinogenesis by limiting their differentiating potential but expanding their proliferative potential. This process is directly connected with stem cell senescence in which DNA alterations play an important role. Cancer stem cells have become the target in treating various cancers. Tumor initiating cells within bladder cancer have been isolated. It has to be tested what connections are between cancer stem cells and tumor initiating cells. Characteristic markers and proteins may help to identify bladder cancer stem cells and thus early stages of bladder cancer. Moreover, bladder cancer stem cells undergo signaling pathways which play critical role both in normal and cancer stem cells.

Introduction and Hypothesis: Regeneration of external urinary sphincter can improve stress urinary incontinence following surgical treatment of prostate cancer. One of the most promising approaches is to force transformation of injected undifferentiated stem cells into muscle phenotype by surrounding tissues, which release paracrine factors. The aim of the study was to determine whether different conditioned media and co-culture system may induce transdifferentiation of bone marrow mesenchymal stem cells (MSCs) in muscle cells. Methods: MSCs were harvested from bone marrow, and cultured for 14d prior differentiation to myogenic lineage protocol. Conditioned media were prepared from skeletal muscle cell line (CRL 1458), and primary muscle precursor cells culture. Co-culture system was prepared from bone marrow mesenchymal stem cells and muscle precursor cells. Mesenchymal stem cells and primary culture of muscle precursor cells phenotype were confirmed by flow cytometry and immunofluorescent labeling. The transdifferentiation process was detected by immunofluorescence studies for calponin, α-actin, desmin, sarcomeric actin and myogenin. Results: At 2 weeks after culturing MSCs in media conditioned with growth factors showed the expression of specific skeletal muscle markers. The level of expression of muscle differentiation markers was higher in comparison to the control (MSCs without conditioned media supplementation). The expression of sarcomeric actin and myogenin was comparable to muscle precursor cells. Skeletal muscle markers as well as polyploid cells formation were observed in MSCs when co-cultured with muscle precursor cells. Conclusion: Transdifferentiation of bone marrow MSCs into skeletal muscle cells can be evoked by growth factors released by neighboring cells building rhabdosphincter.

Cancer cells differ from the other cells by their ability to survive under conditions of enhanced oxidative stress. This property of cancer cells might also be an origin of resistance of tumors to drug treatment. Reactive oxygen species (ROS) overproduction (oxidative stress) might be responsible for both survival and death of cancer cells and the opposite effects of ROS signaling can depend on many reasons. In present work we consider several possible mechanisms of ROS effects on survival/death cancer cells: the different effects of two main reactive oxygen species paramagnetic free radical anion superoxide and diamagnetic molecule hydrogen peroxide, competition between protein kinases and phosphatases, and modification of ROS-depended enzyme/gene cascades. The oxidation of protein kinase B (Akt) by ROS might be of great importance for a shift of the survival to apoptotic signal in the enzymatic cascade. Dual effects of ROS overproduction on cancer cells appear to depend on the levels of oxidative stress: weak/ moderate oxidative stress enhances survival while severe oxidative stress induces cell death. The regulation of ROS overproduction by antioxidants and prooxidants is possibly an important promising way for cancer treatment.

Y-box binding protein 1 (YB-1) is a member of the large protein family with an evolutionarily ancient coldshock domain. It is involved in the regulation of some global traits of malignancy and functions both in the cell nucleus and cytoplasm. We investigated the content of YB-1 mRNA and proportion of cells with YB-1 nuclear localization in breast cancer (BC) tumors taken at mastectomy. We showed that an increased level of YB-1 mRNA in samples correlated with tumor aggressiveness and increased expression of multidrug resistance (MDR) genes. Over-expression of several MDR genes was found in the samples with high YB-1 mRNA content and with YB-1 cytoplasmic localization. This suggests that YB-1 regulates expression of some MDR genes at the level of cytoplasm. The nuclear YB-1 localization also correlated with BC aggressiveness; however, these interconnections were less prominent in comparison with those between a high YB-1 mRNA content and the mentioned tumor characteristics. Our results show that neo-adjuvant chemotherapy induces translocation of YB-1 from the cytoplasm to the cell nucleus in mammary tumors. In the experiments with cell cultures we showed that chemotherapeutic drugs stimulated YB-1 nuclear translocation, as well as MDR genes expression and cell multidrug resistance. We suppose that YB-1 nuclear translocation determines adaptation of tumor cell populations to the environmental impact, while a high YB-1 mRNA content is an intrinsic feature that contributes to the control of the global traits of malignancy. A combination YB-1 mRNA content and its intracellular localization may serve as a test for BC prognosis.

Breast cancer is the second-leading cause of cancer death among women in the United States, alone. Many papers throughout the past and current medical literature have shown it is strongly associated with the reproductive axis and the growth hormone axis. Ghrelin is a pleiotropic 28-aminoacidic hormone and an integrated component of the GH axis, which is implicated in breast cancer risk factors. There has never been published a systematic review about ghrelin, its receptor and gene and their relation to breast cancer till this day, to our knowledge. The main goal of this systematic review is to explore the aforementioned relationship in perspective to new therapeutic targets. A systematic review of relevant studies by searching the PubMed and the SciVerse Scopus databases was performed retrieving four (4) experimental studies, three (3) cohort and one (1) case-control study, which were included in the present systematic review, out of 63 papers. Ghrelin is definitely an auspicious candidate molecule for breast cancer prevention, detection and therapy. Future studies should be encouraged to investigate ghrelin axis on breast cancer pathogenesis and/or tumorigenesis, which hopefully would give results in difficult breast cancer cases, such as in reproductive females.

Many patients suffering from head and neck squamous cell carcinoma (HNSCC) do not benefit from cetuximab added to radiotherapy. Some of the mechansisms leading to resistance to the combined treatment are already understood. However, they do not fully explain the resistance to multimodal therapy. In this review, potential mechanisms of resistance to therapy will be addressed, starting from the outside of the cells looking at the potential role the ECM may play, then continuing with EGF receptor alterations, which may contribute to resistance to therapy with antibodies. The role of FcγRIIIa receptor polymorphism in antibody-dependent cell-mediated cytotoxicity (ADCC), which may be a mechanism of anticancer activity of cetuximab will be discussed, as well as the resistance to radiotherapy and receptor blocking therapy mediated by the insulin-like growth factor receptor I (IGF-1R). Inside the cell, proteins expressed in radioresistant cells will be highlighted before turning the attention to the impact epithelial mesenchymal transition (EMT) may have on increased resistance to different treatment modalities. The last section of this review aims to outline potential treatment approaches, which, in the future, may help improve treatment response.

Even though cancer therapies attain nowadays as many as 10 million survivors, some studies surprisingly report a higher risk of cardiovascular death compared with that of tumor recurrence. Cancer survivors are thus candidates for a thorough cardiovascular evaluation, because they acquire cardiovascular risk together with oncologic cure. VEGF or tyrosinkinase inhibitors, increasingly used in a large variety of tumours with a significant survival advantage, are prototypical drugs simultaneously realizing oncologic care and cardiotoxicity, by targeting angiogenic replicative pathways, involved in both cardiac health and cancer progression. The pathophysiology of cardiovascular disease, mainly consisting in defective angiogenesis, is indeed opposite to that of tumorigenesis and metastasis spreading, both crucially sustained by enhanced blood vessel development. The clinical expression of cardiotoxicity includes not only the development of a dilated hypokinetic cardiomyopathy, currently generally treated with cardiological drugs, but also hypertension, clinical or subclinical atherothrombotic ischemic heart disease and ischemic cardiomyopathy. These clinical syndromes deserve a more adequate cardiovascular assessment and appropriate advanced treatment strategies including percutaneous coronary intervention, coronary artery bypass graft, or device implantation. If not proactively suspected, diagnosed and treated, these manifestations may lead to cardiac events, and reduce overall survival. This review analyzes the available evidence about molecular pathways, predictors and monitoring of impaired angiogenesis-driven cardiotoxicity. Even clinical relevance, pharmacodynamics and markers of efficacy of various intended or “accidental” antiangiogenic drugs will be discussed with the purpose of easing appropriate cardiological surveillance and treatment. Drug tailoring aimed at outcome and cost-effectiveness, according to both drug susceptibility and cardiovascular vulnerability will be finally revised.

Inositol hexaphosphate (IP6, InsP6) is a polyphosphorylated carbohydrate with diverse signaling properties. IP6 is plentiful in organisms as diverse as yeast, actinobacteria, mammals and plants. In the plant kingdom, IP6 accumulates during seed development; during germination it is broken down into lower inositol phosphates and micronutrients to maintain seedling. IP6 is the most abundant of the intracellular inositol phosphates in eukaryotes. In mammals IP6 maintains homeostasis, stores phosphate and acts as a strong anti-oxidant and neurotransmitter. IP6's rapid phosphate turnover properties justify its critical role in cellular pathways involved in signal transduction, control of cell proliferation and differentiation, RNA export, DNA repair, energy transduction and ATP regeneration. The health benefits of IP6 have been demonstrated to lower serum cholesterol level, normalize pathological platelet activity and prevent pathological calcification and kidney stone formation. It is also a potent antioxidant and immunity enhancer. However, it is the field of cancer prevention and therapy that may be the biggest career for IP6. In this review we present updated knowledge on signaling events caused by this fascinating, ubiquitous molecule that has numerous functions.

There is a critical need for the development of novel diagnostic and therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC), a devastating disease known for its poor prognosis due to its late presentation and high aggressiveness. MicroRNAs (miRNAs) are a class of short non-coding RNAs that have been implicated in the gene regulation in normal cellular processes as well as cancer pathogenesis. Patterns of miRNA upregulation and downregulation have been found to be unique to specific cancers, including PDAC. MiRNA expression profiling may serve as a new strategy for the diagnosis and prognosis of PDAC cases. In addition, the role of miRNAs in important cellular processes such as cell development, survival, and proliferation may also be utilized for novel therapeutic approaches. This article presents current progress on the role of miRNAs as a biomarker and therapeutic target for PDAC.