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The current state of the science supporting new research in lysophospholipids The study of lysophospholipids exploded with the discovery of cell surface receptors on both lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). Since then, thousands of original research reports ranging from fundamental cell signaling to the physiology and pathophysiology of individual organ systems have centered on lysophospholipids. This book draws together and analyzes the current literature to provide readers with a state-of-the-science review as well as current techniques that support research in all aspects of the field of lysophospholipid signaling. Lysophospholipid Receptors is divided into three sections: Receptors and other possible effectors Enzymes Physiology and pathophysiology Within each section, the authors explain the similarities and differences between LPA and S1P signaling. Examples are provided that demonstrate the underlying mechanisms of lysophospholipid signaling across a broad range of organ systems, such as S1P signaling in cardiovascular physiology and disease and the neural effects of LPA signaling. Extensive references at the end of each chapter provide a gateway to the literature and facilitate further research into individual topics. Each chapter has been authored by one or more leading international authorities in lysophospholipid research. Based on a thorough analysis of the current research, the authors set forth what is established science and offer their expert opinion and perspective on new and emerging areas of research, setting the stage for further investigations that will solve current problems in the field.
Biological Mechanisms and the Advancing Approaches to Overcoming Cancer Drug Resistance, Volume 12, discusses new approaches that are being undertaken to counteract tumor plasticity, understand and tackle the interactions with the microenvironment, and disrupt the rewiring of malignant cells or bypass biological mechanism of resistance by using targeted radionuclide therapies. This book provides a unique opportunity to the reader to understand the fundamental causes of drug resistance and how different approaches are applied. It is a one-stop-shop to understand why it is so difficult to treat cancer, and why only a very few patients respond to therapy and a significant portion develop resistance. Despite a rapid development of more effective anti-cancer drugs and combination therapies, cancer remains the leading cause of lethality in the developed world. The main reason for this is the ability of heterogeneous subpopulations of tumor cells interacting with constantly evolving tumor microenvironment to resist elimination and eventually, trigger cancer relapse. In this book, experts review current concepts explaining molecular and biological mechanisms of cancer drug resistance and discussing advancing approaches for overcoming these therapeutic challenges. - Provides the most updated knowledge on the mechanisms of cancer drug resistance and the emerging therapeutic approaches reviewed by experts in the field - Brings detailed analyses of most important recently reported developments related to drug resistance and their relevance to overcoming it in cancer patients - Discusses in-depth molecular mechanisms and novel concepts of cancer resistance to conventional and advanced therapies
Systemic chemotherapy in combination with local intervention through surgery and radiotherapy are effective treatments for breast cancers. Chemotherapy is often used in patients with early signs of disease to effectively shrink the tumor and prevent metastasis before surgical excision of the tumor. However, relapse occurs in some of these patients due to the presence of remnant cancer cells that are resistant to chemotherapy. These cancer cells may acquire additional resistance mechanisms resulting in multi-drug resistance and treatment failure. Aggressive tumors show inherently poor sensitivity to chemotherapeutics. Studies primarily based on cell culture models have identified mechanisms of chemo-resistance. These mechanisms include alterations in drug accumulation, increased drug metabolism, altered DNA damage response, evasion of cell-death and decreased ceramide accumulation. In animal models of cancer, additional complexity arises from signaling cross-talk among the cancer cells, stroma, extracellular matrix and the vasculature in the tumor microenvironment that contribute to the development of multi-drug resistance. Cytokines, chemokines and growth factors secreted into the tumor microenvironment represent a hurdle to successful chemotherapy by making the tumors inherently resistant and contributing to development of additional resistance. We examined the mechanism by which extracellular lysophosphatidate (LPA), which is produced by the secreted enzyme, autotaxin (ATX), contributes to multi-drug resistance using breast, thyroid, liver and lung cancer cells. LPA acts through its G-protein coupled receptor, LPA1-6, to promote survival and proliferation in cancers. We discovered that LPA increased the stability and nuclear localization of the transcription factor Nuclear Factor, Erythroid 2-Like 2 or Nrf2. Nrf2, a master regulator of the antioxidant response, promotes resistance to chemotherapeutics through increased metabolism, conjugation and export of drugs from the cell. We showed that LPA, through the activation of LPA1 receptors and phosphatidylinositol 3-kinase (PI3K), increased Nrf2 stabilization and the expression of multi-drug resistance transporters (MDRT) and antioxidant genes. LPA increased the efflux of substrates of the MDRT, which includes chemotherapeutics such as doxorubicin. Consequentially, LPA protected cancer cells from doxorubicin- and etoposideinduced apoptosis. We tested these results in vivo using a syngeneic 4T1 breast cancer model. Blocking LPA production with ONO-8430506, a competitive ATX inhibitor, decreased the expression of Nrf2 and Nrf2-regulated genes in breast tumors. Combining 4 mg/kg doxorubicin every third day with 10 mg/kg ONO- 8430506 every day decreased tumor growth and metastasis to lungs and liver by >70%, whereas doxorubicin alone had no significant effect on tumor growth. Additionally, we show increased expression of Nrf2 in the primary tumors of breast cancer patients, who have a recurrence following surgery and chemotherapy. We also demonstrate a novel concept of chemotherapy-induced increases in inflammation and ATX production as a mediator of resistance to oxidative damage in the 4T1 tumors. Increased expression of Nrf2 and its targets were also observed in tamoxifen-treated breast cancer cells and tumors. Inhibition of ATX overcomes this vicious cycle of inflammation, LPA production and resistance to oxidative damage. Finally, we examined another aspect of LPA signaling that contributes to increased resistance to chemotherapeutics. This involves increased activation and expression of sphingosine kinase 1 (SK1), which results in formation of sphingosine 1-phosphate (S1P) in the cells. LPA-induced translocation of SK1 to membranes, which constitutes an activation step, is higher in doxorubicin-resistant cancer cells when compared to their isogenic controls. Additionally, the doxorubicin-resistant cancer cells have increased expression of the MDRT and S1P receptors. We propose that extracellular LPA coordinates S1P signaling in cancer cells. This is through activation of SK1, secretion of S1P through the MDRT and increased signaling of secreted S1P through the S1P receptors. Overall, our studies have demonstrated a potentially important role for LPA signaling in increasing resistance to chemotherapies and development of multi-drug resistance. This is through the increased expression of Nrf2 and transcription of antioxidant and MDRT genes. Our study also provides a practical strategy for targeting LPA signaling in cancers by blocking LPA production with ATX inhibitors. There are no ATX inhibitors in the clinic. Inhibition of ATX could be a useful strategy in improving the efficacy of existing cancer therapies and to prevent the development of chemo-resistance in patients.
The previous edition of Transmembrane Signaling Protocols was published in 1998. Since then the human genome has been completely sequenced and new methods have been developed for the use of microarrays and proteomics to analyze global changes in gene expression and protein profiles. These advances have increased our ability to understand transmembrane signaling processes in much greater detail. They have also simultaneously enhanced our ability to determine the role of a large number of newly identified molecules in signaling events. In addition, novel video microscopy methods have been developed to image transmembrane signaling events in live cells in real time. In view of these major advances, it is time to update the previous edition. Because of the success of that volume, we have chosen to keep the essential character of the book intact. Introductory chapters from experts have been included to provide overall perspective and an overview of recent advances in signal transduction pathways. The individual chapters now include comp- hensive detailed methods, studies in genetically tractable systems, fluorescence microscopy in live single cells, ex vivo analysis of primary cells from tra- genic mice, as well as genomic and proteomic approaches to the analysis of transmembrane signaling events. We would like to express our deep gratitude to the coauthors of this publi- tion. We hope that Transmembrane Signaling Protocols, Second Edition will serve as a valuable resource for future progress in the study of signal transd- tion pathways.
Phosphoric Acids—Advances in Research and Application: 2012 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about Phosphoric Acids. The editors have built Phosphoric Acids—Advances in Research and Application: 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Phosphoric Acids in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Phosphoric Acids—Advances in Research and Application: 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Autotaxin is a secreted enzyme that produces most of the extracellular lysophosphatidate from lysophosphatidylcholine, the most abundant phospholipid in plasma. Lysophosphatidate mediates many physiological and pathological processes by signaling through six G-protein-coupled receptors to promote cell survival, proliferation and migration. Knocking out autotaxin in mice is embryonically lethal as a result of impaired vasculogenesis and improper neural-crest folding. In the post-natal organism, autotaxin/ lysophosphatidate signaling mediates wound healing and tissue remodeling through acute inflammatory processes. However, in chronic inflammation, this signaling drives many diseases including rheumatoid arthritis, hepatitis, colitis, asthma and cancer. In cancer, lysophosphatidate promotes cell proliferation and migration, angiogenesis, metastasis and chemotherapy and radiotherapy resistance. Currently, there are no therapies targeting lysophosphatidiate signaling and this provides an opportunity for introducing new cancer treatments. Because most lysophosphatidate is produced by autotaxin activity, an inhibitor of the autotaxin catalytic site would block subsequent lysophosphatidate signaling. Therefore, it is important to understand how autotaxin activity is regulated by lysophosphatidate. It has been proposed that autotaxin is product-inhibited by lysophosphatidate or a related lipid called sphingosine-1-phosphate. This has led to the design of several lipid-mimetic autotaxin inhibitors. We now show that this competitive inhibition is ineffective at high concentrations of lysophosphatidylcholine that occur in vivo. Instead, lysophosphatidate and sphingosine-1-phosphate inhibit autotaxin expression through phosphatidylinositol-3-kinase activation. However, this physiological inhibition is overcome by inflammatory-mediated signaling. We propose that inflammation is vital for pathological autotaxin and lysophosphatidate production, and lysophosphatidate signaling in turn further drives an inflammatory environment. Consequently, an autotaxin inhibitor should be able to break this vicious cycle. However, this hypothesis has not been tested as historical autotaxin inhibitors have poor bioavailability profiles. We tested a novel non-lipid-mimetic ATX inhibitor (ONO-8430506) in mice which decreases plasma autotaxin activity by >80% and concentrations of unsaturated lysophosphatidates by >75% for 24 h. We also showed for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastasis in a 4T1/Balb/c syngeneic orthotopic breast cancer mouse model by 60% compared to vehicle-treatment. When combined with doxorubicin, ONO-8430506 synergistically decreases tumor growth and lung and liver metastases by >70%, whereas doxorubicin alone had marginal effects. Significantly, 4T1 breast cancer cells express neglible autotaxin compared to the mammary fat pad. Autotaxin activity in the fat pad of non-treated mice is increased 2-fold by tumor growth. This increase correlates with increases in inflammatory chemokine and cytokine production that is suppressed by ATX inhibition. We also extended our studies of autotaxin-mediated cancer growth and inhibition to papillary thyroid cancer. The diagnosis of thyroid cancer by fine needle biopsies is imprecise in ≥25% of cases resulting in unnecessary surgery. Many thyroid cancer patients also become resistant to radiotherapy and chemotherapy. Our work addresses both of these problems. We demonstrate that high expression of inflammatory chemokines and cytokines and increased secretion of autotaxin by thyroid cancer cells provides a definitive identification of human papillary thyroid cancer from benign nodules. Autotaxin secretion is hijacked in thyroid cancer in a vicious inflammatory cycle in which lysophosphatidate stimulates autocrine chemokine and cytokine secretion. This in turn increases autocrine autotaxin production. We show that treating mice daily with ONO-8430506 decreases thyroid tumor growth in xenograft models by >50%. There were also decreases in multiple inflammatory chemokines and cytokines, platelet-derived growth factor and vascular endothelial growth factor in the tumors. This results in decreased cancer cell division and angiogenesis. Therefore, regardless of whether autotaxin is produced in an autocrine fashion like in thyroid cancer or in a paracrine manner like in breast cancer, this work describes a new paradigm where autotaxin secretion is inflammatory-mediated and an autotaxin inhibitor is therapeutically effective. Autotaxin inhibitors have great potential to improve cancer patient outcomes and we propose that they also could have utility in other chronic inflammatory-mediated conditions.
Phospholipases in Physiology and Pathology presents a comprehensive overview on the physiology and pathology of phospholipases. This seven-volume set considers the biochemical and molecular mechanisms of normal and abnormal cell function upon dysregulation of phospholipases in different diseases. Volumes cover signal transduction mechanisms, implications in cancer, infectious diseases, neural diseases, cardiovascular diseases and other diseases, implications in inflammation, apoptosis, gene expression and non-coding RNAs, the role of natural and synthetic compounds, and stem cell therapies, nanotechnology-based therapies, and more. Together, these volumes give researchers critical insight on the mechanistic and therapeutic aspects of phospholipases. Discusses the biochemical and molecular mechanisms of normal and abnormal cell function in different disease processes Covers a wide range of basic and translational research appropriate for scientists engaged in studying the regulation of phospholipases from interdisciplinary perspectives Features state-of-the-art chapter contributions from international leaders in the field
This book contains conference presentations regarding the regulation of eicosanoid enzymes and, in particular, cyclooxygenases, lipoxygenases, and phospholipases. The new field of isoprostanes is also represented.