Current Signal Transduction Therapy - Volume 3, Issue 2, 2008

Liver X Receptor-α (LXRα, also known as NR1H3) and LXRβ (NR1H2) are members of the nuclear receptor superfamily of ligand-activated transcription factors, a superfamily which includes the more widely known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. The LXRs are activated by physiologic sterol ligands (e.g., oxysterols) and by synthetic agonists. In recent years, our understanding of the importance of LXRs has expanded across several fields of (patho-) physiology. Perhaps best known from a sizeable literature as homeostatic ‘cholesterol sensors’ that drive transcriptional programs promoting cellular cholesterol efflux, ‘reverse cholesterol transport,’ and bile acid synthesis, more recent roles for LXRs in glucose homeostasis, atherosclerosis, and innate immunity have also been identified. These discoveries complement an emerging literature that continues to draw surprisingly intimate connections between host metabolism and host defense. The present review will discuss the roles of LXR in the signaling of metabolism and innate immunity, and the potential for synthetic LXR agonists as novel therapeutics in dyslipidemia, atherosclerosis, disordered glucose metabolism, and inflammation.

The popularity of medicinal herbs has grown significantly in recent years despite a dearth of information regarding their modes of action and continuing concerns over their efficacy. Recent efforts to elucidate the mechanisms of action of several anti-inflammatory herbs have focused on a class of compounds, sesquiterpene lactones, that are believed to be the active components of these herbal medicines. Sesquiterpene lactones constitute a large and diverse group of biologically active plant constituents that have been reported from the Acanthaceae, Anacardiaceae, Apiaceae, Euphorbiaceae, Lauraceae, Magnoliaceae, Menispermaceae, Rutaceae, Winteraceae and the Hepatidae (liverworts). However, the greatest number has been reported from the Asteraceae. Tanacetum parthenium (feverfew) is one of the most prominent species in the Asteraceae and a known remedy for the treatment of various diseases. Feverfew has been used for at least two millennia for the treatment of fever, as well as headache, menstrual irregularities and stomach-ache. Today, feverfew is widely used as a migraine preventive, and more recently as an aid for those suffering from arthritis and inflammation. The drug feverfew contains a series of compounds, particularly sesquiterpene lactones, which, being parthenolide, are regarded as the main cause of the therapeutic properties of the plant. Although a few studies have been published which evaluate the effects of parthenolide in vivo, several studies have been undertaken to investigate the molecular basis of the pharmacological effect of parthenolide. This review will summarize some of the most important reports on the role of parthenolide in intracellular signalling processes from the literature data (2004-2007).

Formyl-peptide receptors (FPR) are expressed in several cell types including phagocytic leukocytes, and a wide variety of agonists of FPR and of its FPRL1 variant have been identified. These ligands interact with their specific receptors on the cellular membrane, and activate specific biological functions through a G-protein-coupled pathway. In nonphagocytic cells, agonist/FPR binding also induces transactivation of the constitutive membrane receptors PDGF-R, EGF-R and uPAR that in turn trigger specific, characteristic intracellular signal transduction pathways. The second messengers resulting from the interaction between ligands and formyl-peptide receptors act on various intracellular kinases (mitogen-activated protein kinases, protein kinases C and B, Jun kinase and some tyrosine kinases). Activation of NADPH oxidase expressed in nonphagocytic cells, and phosphorylation and nuclear translocation of regulatory transcriptional factors may be the downstream targets of this signaling cascade. The activated signal transduction pathways also lead to various biochemical cellular responses that can contribute to cell proliferation, and can protect against cell death and the malignant behavior of several human cancer cell lines. Dissection of the signaling cascade triggered by different agonists will shed light on the role of FPRs in nonphagocytic cells in both human physiology and diseases.

Approximately 80% of the kidney is composed of tubular cells which secret and reabsorb substances to and from the urine. Activated tubular cells play a pivotal role in the etiology of renal fibrosis. During renal injury, these activated tubular cells participate in the initiation of fibrogenic processes which eventually may lead to tubulointerstitial fibrosis and end stage renal disease (ESRD). Current therapies such as angiotensin converting enzyme inhibitors, angiotensin II receptor type-1 antagonists and statins do not suffice for the treatment of renal fibrosis. However, in recent years, better understanding of disease mechanisms led to the development of new drug entities that intervene in the signal transduction pathways involved in the disease pathogenesis. This review discusses possible new drugs directed to intracellular signal transduction pathways such as mitogen-activated protein kinases (p38, ERK and JNK), growth factors receptor tyrosine kinases (TGF-β and PDGF), Rho kinase, and nuclear transcription factors that are activated during disease. In addition to kinase inhibitors, novel approaches such as renal-selective drug targeting, recombinant protein antifibrotic agents and gene silencing concepts are discussed.

According to the American Cancer Society, Prostate cancer (PCa) is the second leading cause of cancer deaths in men. Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is no cure once the disease has spread beyond the prostate. Androgens are the primary growth factors used by prostate cancer cells initially, and androgen deprivation remains the only treatment for men with clinically advanced stage disease; however, prostate cancer cells eventually progress to androgen independence, and androgen refractory prostate cancer is ultimately responsible for the death of PCa patients. There is at present no effective treatment for hormone-independent PCa. Normal prostate epithelial cells as well as early-stage-prostate cancer cells depend on androgens for growth and survival. However, several molecular mechanisms like mutations to the androgen receptor (AR), cross-talk between the AR and other molecular pathways can lead to an independence from androgens for growth. These casual molecular genetic changes lead to an epigenetic mechanism where a feed-back autocrine loop between membrane receptors and associated ligands serves as an essential component of growth, proliferation and metastasis of prostate cancer at an advanced and androgen-independent stage. Peptide growth factors and cytokines are known to exert their effects by a complex array of mechanisms primarily mediated by signal transduction pathways. Thus, we rationalized that inhibiting these epigenetic events could serve as an approach in treatment of advanced prostate cancer. In this article we have reviewed all the relevant literature that describe signal transduction pathways in prostate gland under normal and malignant conditions. We will also try to identify possible signal transduction targets for the treatment of prostate cancer.

Overexpression of the leucine-rich, glioma-inactivated 1 (LGI1) gene in neuroblastoma cells inhibited proliferation and efficiently induced apoptosis. Cell clones stably transfected with LGI1 cDNA showed greater mortality during a period of serum starvation in comparison with control cells stably transfected with empty vector. This observation suggested hindrance of the PI3K/Akt pathway, a central transducer of survival stimuli elicited by serum growth factors. Treatment with inhibitors of PI3K significantly increased the death of control cells but substantially failed to influence LGI1 cell death, which was greatest independently of the presence of inhibitors. Blockage of the PI3K/Akt pathway in LGI1 cells was confirmed by the lack of serum-induced Akt phosphorylation, in contrast with the strong response of control cells. Instead, serum-induced phosphorylation of ERK1/2 was not impaired by the expression of LGI1. This study showed that overexpression of LGI1 caused neuroblastoma cell death by blocking activation of the PI3K/Akt pathway. Thus, the possibility of upregulating LGI1 expression may be a novel strategy in suppressing oncogenesis and metastasis sustained by excessive activation of the PI3K/Akt pathway.

Dendritic cells (DCs) play a crucial role in translating innate to adaptive immunity. DC-based cancer immunotherapy has been under evaluation; however, its clinical benefits remain limited. A better understanding of DCs is, therefore, needed to improve clinical outcomes. Toll-like receptors (TLRs) were initially identified as molecules that recognize and bind pathogen-associated molecular patterns (PAMPs) leading to DC maturation. The TLR signaling pathway leads to the activation of NF-κB, which initiates the transcription of proinflammatory cytokine genes. As the sensors of RNA viruses in the cellular cytoplasm, RNA helicases containing retinoic acidinducible gene-I (RIG-I) have been shown to recognize the viral RNA genome, and recent studies have demonstrated that these helicases strongly induce the upregulation of type I interferons. We recently demonstrated that RNA viruses strongly activated DCs, and this finding is expected to aid in the development of improved DC-based cancer immunotherapy. We then proposed DC-based “immunostimulatory RNA virotherapy” as a novel therapeutic approach. The janus kinases (JAKs) and the signal transducers and activators of transcription (STATs) are key molecules in a major signaling pathway for modulating DC function; suppressors of cytokine signaling (SOCSs) inhibit this pathway. Some recent studies have suggested that the suppression of SOCS family proteins in DCs modulates immune responses, including anticancer immunity. Here, we review recent progress in the elucidation of the mechanisms of signal transduction pathways in DCs; it is hoped that such investigations will eventually lead to a variety of DC-based cancer immunotherapies.

The growth factor signals regulate the balance of cell proliferation and cell death to maintain the homeostasis in vivo; hence, deregulation of the balance underlies a variety of human diseases. The PI3K-Akt network is activated by various cytokines or growth factors and mediates intracellular signals to regulate a wide variety of cellular responses, including anti-apoptosis, proliferation, cell cycling, protein synthesis, glucose metabolism, and telomere activity. Genomic mutations, alterations, amplifications, and/or translocations of the oncogenes, tumor suppressor genes, or kinases involved in the PI3K-Akt regulatory network underlie various human diseases such as cancers, viral infections, glucose intolerance (or diabetes mellitus), schizophrenia, and/or autoimmune diseases. Therefore, targeting the PI3K-Akt network becomes an attractive goal for drug development.This review article summarizes the current knowledge about the regulation of the PI3K-Akt signaling network to highlight therapeutic implications for human diseases.