Current Signal Transduction Therapy - Volume 8, Issue 2, 2013

Phosphoinositide 3-kinases (PI3Ks) play an essential role in the intracellular signal transduction cascades initiated by the activation of cell surface receptors through their specific extracellular signals. PI3Ks control a variety of cellular responses, including growth, protection from apoptosis, motility, metabolism and intracellular protein sorting. Eight catalytic PI3K isoforms exist in human, which are grouped into three classes (I-III), based on structural homology and in vitro substrate specificity. Class I PI3Ks mediate signalling by receptor tyrosine kinases (RTKs) and G-proteincoupled receptors (GPCRs). The class II of PI3Ks, which comprises three distinct isoforms (PI3KC2α, PI3KC2β and PI3KC2γ) are less well characterized in terms of cellular functions. PI3KC2α and PI3KC2β are activated downstream of RTKs and GPCRs and play a role in cell migration, survival, glucose transport and endocytosis. Recently, the first isoform-specific small molecule inhibitors of PI3KC2β were described and evaluated as anti-proliferative agents in cancer. In this review, we will discuss the different regulatory mechanisms and functions of class II PI3Ks in the context of cell surface receptor signalling and their potential as novel drug targets in the field of oncology.

Brefeldin A (BFA) is an fungal antibiotic that induces ER stress in eukaryotic cells. Cancer stem cells (CSCs) have indefinite potential for self-renewal and the capability to drive tumorigenesis. The effects of BFA on CSCs have not been fully investigated. In this article we investigated the inhibitory effects of BFA on human lung cancer A549 and H1299 cells. Cytotoxicity toward suspension cultures has been used as a method for the preliminary screening of drugs targeting CSCs. We showed that BFA effectively reduced the survival of suspension A549 cells (EC50 =~30 ng/ml) by inducing apoptosis, and inhibited the clonogenic activity of A549 and H1299 CSCs at the same concentration range. We also demonstrated that BFA reduced the migration ability of A549 and H1299 cells. These results suggest that BFA can effectively suppress the progression of lung cancer during tumorigenesis and metastasis. The results of this study may help develop novel therapy for future treatment of lung cancer.

The NMDA receptor non-competitive antagonist ketamine is regarded to model multiple symptomatic domains and molecular dysfunctions of schizophrenia, depending on acute or chronic exposure to the drug. In this work, we aimed to investigate whether ketamine may induce changes in the expression of transcripts relevant for the dopaminergic system (i.e. dopamine D1, D1R, and D2 receptors, D2R, dopamine transporter, DAT) and whether these changes were differentially modulated by acute vs. subchronic exposure. Acute ketamine decreased D1R expression in the ventrolateral caudate-putamen. Subchronic ketamine did not affect D1R and D2R expression. Increased D2R and DAT expression by subchronic ketamine was found in the midbrain. Distribution of mRNA expression showed sharp differences after acute vs. subchronic treatments for all transcripts. Subchronic ketamine induced an upergulation of D2R and DAT mRNA transcripts in the midbrain, since expression was significantly increased compared to both subchronic and acute vehicle-mediated expression. The observed molecular changes by acute vs. subchronic ketamine may model different steps in psychosis pathophysiology involving dopaminergic system.

Protein tyrosine phosphatases (PTPs) are important in the regulation of diverse cellular functions including proliferation, migration and invasion; aberration of these cellular events is crucial for the development and progression of cancer. PTPs family comprises of two groups, classic PTPs and dual specificity phosphatases. The classic PTPs include both non-transmembrane PTPs and transmembrane receptor-like PTPs (RPTPs). RPTPs are composed of extracellular regions, transmembrane domains and intracellular phosphatase domains. The extracellular regions of RPTPs are similar to cell adhesion molecules and can interact homophilically and heterophilically. There are eight subgroups in the RPTPs separated according to the differences in their extracellular regions. PTPRK and PTPRM belong to the R2B subfamily of RPTPs and both perform homophilic interactions and regulate cell-cell aggregation and adhesion. Furthermore, both PTPRK and PTPRM can interact with the catenin/cadherin complex to regulate cell proliferation and migration. The current review discusses the present knowledge on RPTPs and their potential implication in the development and progression of cancer.

Cytoskeleton is a major component of living cells consisting of microfilaments, microtubules and intermediate filaments. It plays a key role in many cell functions such as cell migration, cell division, signal transduction and cell apoptosis. Researchers have investigated the cytoskeleton by analyzing its molecular components in isolation and studying its ‘gel’ properties. The proposal of tensegrity model firstly considers the cytoskeleton as a whole architectural structure to investigate cellular behaviors in response to mechanical stimulation. Furthermore, recent studies have suggested that cytoskeleton may function as electric cables and plays an important role in cellular responses to electric fields. In this review, we summarize recent studies about the role of cytoskeleton in view of tensegrity and discuss how cytoskeleton functions as cables in cellular response to electric fields. Understanding this process will be helpful to find out the detail of electroporation and other electric effect by application of electric stimulation.

Natural products play a crucial role in research into innovative antiproliferative agents. More than 60% of anticancer drugs involve compounds of natural origin. The aim of the present study was to determine the cytotoxicity effects of 11 quinoline alkaloids isolated from plants of the Rutaceae family. The MTT assay was used to identify the antiproliferative effects of the tested compounds on human adherent cancer cell lines (HeLa, A431, MCF7 and A2780). Two of these alkaloids, kokusaginine and skimmianine, were found to inhibit the proliferation of cancer cells and to induce a cell cycle arrest in a concentration-dependent manner in HeLa cells, as evidenced by flow cytometry. A noncancerous human fibroblast cell line (MRC-5) was used to test the selectivity of kokusaginine and skimmianine. Fluorescent microscopy after Hoechst 33258 + propidium iodide double staining revealed concentration-dependent nuclear condensation and disturbed cell membrane integrity. The apoptotic potentials of kokusaginine and skimmianine were proved by assaying caspase-3. The presented results demonstrate that kokusaginine and skimmianine can be recommended as appropriate starting structures for the design and synthesis of further quinoline analogs with improved efficacy.

Protein kinases function in key steps in several physiopathological events; therefore the development of specific inhibitors to these enzymes presents new opportunities for the treatment of various diseases. Glycogen synthase kinase 3 (GSK-3) is a constitutively active serine/threonine kinase, whose dysfunction has been linked to several cases of insulin-resistant type 2 diabetes mellitus, Alzheimer’s disease and mood disorders. These findings make GSK-3 an attractive target for therapeutics, and several research groups and pharmaceutical companies have made significant efforts to develop new inhibitors with selective activity to different GSK-3 pathways. One of the strategies applied in the development of new inhibitors is based on protein-protein interactions between substrates or docking proteins of specific proteins kinases, creating peptides modulators designed to specifically inhibit those enzymes. Here, we discuss the development, signaling and the patent applications of specific peptides designed to inhibit GSK-3, their patent status and their potential uses in the treatment of GSK-3 specific pathologies.

Our previous studies demonstrated that Qi-Shao-Shuang-Gan (QSSG), a combination of Astragalus membranaceus saponins (SAM) with Paeonia lactiflora glycosides (GPL), possessed protective effects against sepsis in mice. The present study aimed to explore its underlying mechanisms with a focus on the adhesion between leukocytes and inflammatory endothelial cells. Our results showed that QSSG (10, 30, 100 μg/ml) concentration-dependently inhibited the adhesion between leukocytes and lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), and downregulated the expressions of endothelial adhesion molecules such as E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in HUVECs. It also suppresssed the phosphorylations of JNK, ERK and p38 MAPK, as well as the activation of NF-κB in HUVECs. The findings revealed that QSSG was able to prevent the adhesion between leukocytes and endothelial cells, which supported a plausible explanation for the antiseptic effects of QSSG.

Current studies have found that allogenic mesenchymal stem cells (MSCs) transplantation (MSCT) can be used successfully in mouse and human SLE. However, syngeneic bone marrow (BM)-MSCT was ineffective. Recently, studies also revealed that BM-MSCs from SLE patients showed senescent behavior. These findings suggested that the senescence of BM-MSCs from SLE patients may be a contributing factor to disease pathogenesis. So further findings about MSCs senescence of SLE will contribute to lay the groundwork for the development of new therapeutic approaches to treat SLE. In this review, we summarize the characteristics of MSCs, molecular mechanisms and signaling involved in MSCs senescence and the senescent biological behavior of MSCs from SLE and possible mechanisms. Analyzing the mechanisms of controlling MSCs senescence may provide a therapeutic target for SLE.