Current Signal Transduction Therapy

ISSN: 1574-3624

Current Signal Transduction Therapy
Volume 1, Number 3, September 2006

Contents


STAT3: A Molecular Target for Cancer Whose Time Has Come Pp. 239-253
Beverly E. Barton
[Abstract]


n-3 Polyunsaturated Fatty Acids as Signal Transduction Modulators and Therapeutical Agents in Cancer Pp. 255-271
Gabriella Calviello, Simona Serini and Paola Palozza
[Abstract]


Emerging Role of Stromal Fibroblasts in Epithelial Cancer Pp. 273-283
Maria Rita Rippo, Antonio Procopio and Alfonso Catalano
[Abstract]


Targeting Prenylated RAS Modifying Enzymes in Cancer Cells Pp. 285-293
Yulong L. Chen
[Abstract]


Targeting Phospholipase D-mediated Survival Signals in Cancer Pp. 295-303
David A. Foster
[Abstract]


The Role of Heat Shock Protein 90 and Endothelial Nitric Oxide Synthase Signaling in Cardiovascular Therapy Pp. 305-315
Tennille Presley, Periannan Kuppusamy, Jay L. Zweier and Govindasamy Ilangovan
[Abstract]


PDX-1 and MafA as Potential Therapeutic Targets for Diabetes Pp. 317-324
Hideaki Kaneto, Takeshi Miyatsuka and Taka-aki Matsuoka
[Abstract]


Carotenoids as Modulators of Intracellular Signaling Pathways Pp. 325-335
Paola Palozza, Simona Serini and Gabriella Calviello
[Abstract]


Biology and Impact of Signal Transducers and Activators of Transcription and Their Regulators as Targets in Cancer Therapy Pp. 337-351
Edith Pfitzner, Frank Nonnenmacher and Daniela Baus
[Abstract]




Abstracts

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STAT3: A Molecular Target for Cancer Whose Time Has Come
Beverly E. Barton

Signal transducer and activator of transcription (STAT) proteins are latent cytoplasmic proteins that transmit cell-surface signals generated by ligand-receptor interactions to the nucleus. They are activated mainly by phosphorylation. Of the STAT proteins, STAT3 and to a lesser extent STAT5, is associated with transformed cells, particularly in tumors arising from oncogenes that activate tyrosine kinase signaling pathways. In benign cells, STAT3 like other STAT proteins, is transiently activated then deactivated by multiple regulatory proteins. However, in many malignant cells, the activation of STAT3 is constitutive; this persistent and aberrant signaling by STAT3 results in the continued expression of anti-apoptotic genes of the bcl family and of survivin, cell-cycling genes, angiogenic factors such as VEGF, and metastasis-promoting factors such as matrix metalloproteases. The activity of some oncogenic viral proteins, notably v-src, is due to persistent activation of STAT3. When malignant cells express constitutive STAT3 activation, their very survival depends upon STAT3’s continued activation or expression or DNA-binding activity; inhibiting STAT3 at any of these steps results in cancer cell apoptosis, whereas benign cells survive the same treatment. This review will discuss the critical role of persistent STAT3 in the maintenance of the malignant state, and the efforts published to date for inhibiting STAT3 as a future therapeutic approach for cancer treatment; limitations of each inhibitory strategy will be included in so far as information is available.


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n-3 Polyunsaturated Fatty Acids as Signal Transduction Modulators and Therapeutical Agents in Cancer
Gabriella Calviello, Simona Serini and Paola Palozza

Epidemiological and experimental studies have established the beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) on cancer. In particular, wide information is available regarding their effects on hormone responsive tumors, such as prostatic and mammary cancer, and tumors originating from colon. Recent studies have focused upon the improvement of chemotherapy effects when different drug treatments are accompanied by n-3 PUFA administration. The growth inhibitory action elicited by these fatty acids on tumors seems to be related to their ability to induce apoptosis and cell cycle arrest in cancer cells and to inhibit neo-angiogenesis. Different molecular mechanisms have been hypothesized to explain their anticancer effects, and this field is receiving increased attention. For a long time n-3 PUFAs have been considered to function only as prooxidant agents, competitors for arachidonic acid metabolism, or modifiers of membrane microenvironment and fluidity in cells. However, more recently, they have been shown to act as transcription regulators, being able to modulate the activity of different transcription factors, including NFkB, peroxisome proliferator-activated receptors, retinoid X receptors, and HIF-1. The expression of a wide array of genes involved in the regulation of cell proliferation, apoptosis, neo-angiogenesis and invasion of tumors have been shown to be modulated by n-3 PUFAs (proteins of BCL-2 family, cyclins and cyclin dependent kinase inhibitors, protein-kinases and phosphatases, COX-2, 5-LOX, VEGF and matrix-metalloproteinases). The modulating action brought about by n-3 PUFAs on the expression of lipid metabolism enzymes, such as fatty acids synthase and 3-hydroxy-3-methyl-glutaryl-CoA (HMG)-CoA reductase, have been recently involved in the anticarcinogenic action of these fatty acids. Telomerases, DNA topoisomerases and DNA polymerases are further molecular targets critical in the growth and survival of cancer cells recently observed to be modulated by n-3 PUFAs. The aim of this review is to examine the molecular mechanisms invoked so far in order to explain the anticancer effects of n-3 PUFAs. The definitive comprehension of the molecular mechanisms involved appears to be crucial to establish the appropriateness of n-3 PUFAs as chemopreventive or adjuvant therapeutic agents in human cancer.


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Emerging Role of Stromal Fibroblasts in Epithelial Cancer
Maria Rita Rippo, Antonio Procopio and Alfonso Catalano

The mechanisms involved in the tumor-stroma interaction during carcinoma progression are an area of intensive investigation. Cancer cells produce a range of growth factors and proteolytic enzymes that modify their stromal environment. These factors disrupt normal tissue homeostasis and act in a paracrine manner to induce angiogenesis and inflammation, as well as activation of surrounding stromal cell types such as fibroblasts, smooth-muscle cells and adipocytes, leading to the secretion of additional growth factors and proteases. Recent studies reveal that fibroblasts have more profound influence on the development and progression of carcinoma than was previously appreciated. These cancer-associated fibroblasts (CAFs) are a heterogeneous fibroblast population with different life-span which are activated and recruited during carcinoma progression. One of the more provocative implications is that genetically altered or/and senescence fibroblasts can induce epithelial cells to form carcinomas. In this article, we will review some evidences that CAFs produce a number of paracrine factors that affect several aspects of pleural and urothelial cancer progression. Moreover, we discuss how this new perspectives on the role of CAFs during cancer initiation and progression can have important implications to cancer therapy.


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Targeting Prenylated RAS Modifying Enzymes in Cancer Cells
Yulong L. Chen

RAS oncogenes have been identified in about 30% of all human cancers, particularly in 90% of human pancreatic cancers, 50% of colorectal tumors, and 30% of lung cancers. RAS is a central switch for many signal transduction pathways. The RAS proteins undergo three major posttranslational modification steps to become fully functional: prenylation (farnesylation or geranylgeranylation) of the cysteine residue of the CAAX of the RAS C-terminus (C, cysteine, A, aliphatic amino acid; X, Ser, Met, Glu, and Leu), endoproteolysis to remove the AAX amino acid sequence, and methylation of the newly formed prenylated cysteine C-terminus. It is hypothesized that any of these three steps could be an interference point for targeting RAS signaling to block the growth of the mutant RAS-dominant cancer cells. In the last decade, intensive efforts have been directed to target the prenylation of RAS, resulting in many RAS farnesylation inhibitors, which are in the clinical trials with mixed results. On the other hand, both recent chemical genetic and traditional genetic studies demonstrate that targeting two prenylation-dependent modification enzymes, RAS endoprotease and methyltransferase, might be two additional targets in killing mutant RAS-dependent cancer cells. This mini-review discusses the implications of both RAS endoprotease and methyltransferase as anticancer targets and their respective inhibitors as anticancer agents in cancer therapy.


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Targeting Phospholipase D-mediated Survival Signals in Cancer
David A. Foster

An important component of tumor progression is the generation of “survival signals” that suppress default apoptotic programs. Survival signals are ideal targets for anticancer therapeutic strategies because blocking survival signals, in principle, can resurrect the apoptotic signals that are suppressed in cancer cells. Phospholipase D (PLD) activity, which is elevated in a large variety of cancers, generates a survival signal that has been shown to suppress apoptosis in human breast cancer cells. Phosphatidic acid, the metabolic product of PLD activity, contributes to the activation of mTOR (the mammalian target of rapamycin), which has been widely implicated in cancer survival signals. Elevated PLD activity suppresses the tumor suppressors p53, Rb and protein phosphatase 2A, and also causes Myc stabilization – indicating that PLD activity is a key regulator of the cellular machinery that controls cell cycle progression. The ability of PLD to suppress apoptosis makes PLD signal transduction an ideal target for therapeutic intervention in the apparent large number of cancers that have elevated PLD activity. As the era of molecular medicine and pathology evolves, it will be possible to identify individual tumors with elevated PLD activity and target either the signals that activate PLD or the downstream targets of PLD. In this review, the emerging paradigm of PLD survival signals is discussed in the context of therapeutic intervention.


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The Role of Heat Shock Protein 90 and Endothelial Nitric Oxide Synthase Signaling in Cardiovascular Therapy
Tennille Presley, Periannan Kuppusamy, Jay L. Zweier and Govindasamy Ilangovan

The 90 kDa heat shock protein, Hsp90, is a critical protein in eukaryotes. Mainly cytosolic, this protein is expressed at extraordinary levels and participates in the folding of specific protein substrates. Hsp90 is well preserved and exhibits a chaperone role in the conformational maturation in the cellular stress response, and the nuclear hormone receptors and protein kinases. This protein regulates signal transducing molecules, which include members of the Src-kinase family of non-receptor tyrosine kinases, serine/threonine kinases and transcription factors. Hsp90 plays an important role in nitric oxide (NO) production and the activation of all of the isoforms of nitric oxide synthase (NOS). This heat shock protein forms a complex with NOS and facilitates its phosphorylation; thus, NO production from the enzyme is enhanced. The formation of NO improves cardiovascular endothelial functions. Studies have shown that an overexpression of Hsp90 regulates oxygen metabolism in the heart through the regulation of NOS. In particular, the Hsp90-eNOS complex augments the activation of eNOS. Hsp90 associates with eNOS under inactive conditions, and upon the stimulation of endothelial cells with VEGF, estrogen, histamine, shear stress, and statins. Thus, understanding the complete role of Hsp90 signaling in cardiovascular systems will help to develop therapeutic approaches to cure many cardiovascular diseases such as ischemia/reperfusion injuries, atherosclerosis, congestive heart failure etc.


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PDX-1 and MafA as Potential Therapeutic Targets for Diabetes
Hideaki Kaneto, Takeshi Miyatsuka and Taka-aki Matsuoka

Pancreatic and duodenal homeobox factor-1 (PDX-1) plays a crucial role in pancreas development and β-cell differentiation, and functions as an activator of insulin gene transcription. MafA is a recently isolated β-cell-specific transcription factor which functions as a potent activator of insulin gene transcription. PDX-1 and MafA play crucial roles in inducing insulin-producing cells from non-β-cells and could be therapeutic targets for diabetes. On the other hand, expression and/or activities of PDX-1 and MafA in β-cells are reduced under diabetic conditions. Alteration of such transcription factors leads to suppression of insulin biosynthesis and secretion and thus explains, at least in part, the molecular mechanism for β-cell glucose toxicity.


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Carotenoids as Modulators of Intracellular Signaling Pathways
Paola Palozza, Simona Serini and Gabriella Calviello

Carotenoids have been proposed to exert beneficial effects in several chronic diseases, including cancer and cardiovascular diseases. Many of the biological actions of carotenoids have been attributed to their antioxidant properties, through the antioxidant capacity of the carotenoid molecule per se or through their possible influences on intracellular redox status. However, the exact mechanism by which carotenoids exert their beneficial effects are still under debate. Increasing evidence shows that carotenoids, and their metabolites, may modulate molecular pathways involved in cell proliferation, acting at Akt, tyrosine kinases, mitogen activated protein kinase (MAP kinase) and growth factor signaling cascades. Moreover, there is now strong evidence for an involvement of carotenoids in the regulation of apoptosis through modulatory effects on the activation of caspase cascade and on the expression of Bcl-2 family proteins and transcription factors. Inhibitory or stimulatory actions at these pathways are likely to affect cellular functions by altering the phosphorylation state of target molecules and by modulating gene expression. A clear understanding of the mechanisms of action of carotenoids, either as redox agents or modulators of cell signaling and the influence of their metabolism on these properties is key to the evaluation of these biomolecules as anticancer and cardioprotective agents.


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Biology and Impact of Signal Transducers and Activators of Transcription and Their Regulators as Targets in Cancer Therapy
Edith Pfitzner, Frank Nonnenmacher and Daniela Baus

While chemo- and radiotherapy is far developed and successfully employed by default for cancer treatment, severe side effects point to the urgent need for more specific therapies based on the molecular mechanisms of this disease. Strategies to specifically inhibit signaling pathways that are known to force proliferation, prevent apoptosis or promote angiogenesis are expected to have a substantial impact on the future direction taken in cancer therapy. The Janus Kinase (JAK) / Signal transducer and activator of transcription (STAT) pathway is one major signaling pathway converting the signal of cytokines, growth factors and hormones into gene expression programs regulating essential cellular functions like proliferation, differentiation and survival. The suppressors of cytokine signaling (SOCS) as well as phosphatases normally tightly regulate the JAK/STAT pathway. Frequently, however this pathway is constitutively activated in a wide variety of human malignancies and substantially contributes to carcinogenesis. Consequently, new strategies for targeting the JAK/STAT pathway have been developed. This review discusses the biology of the JAK/STAT signaling pathway, which offers several molecular strategies for therapeutic interruption.