Bin Liu

University of Florida | UF · Department of Pharmacodynamics

Alcohol overconsumption is a major cause of preventable mental disorders and death in the United States and around the world. The pathogenesis of alcohol dependence, abuse, and toxicity to the central nervous system remains incompletely understood. Cell culture-based models have been highly valuable in studying the molecular and cellular mechanisms...

As the resident immune cells in the central nervous system, microglia play an important role in the maintenance of its homeostasis. Dysregulation of microglia has been associated with the development and maintenance of chronic pain. However, the relevant molecular pathways remain poorly defined. In this study, we used a mass spectrometry-based prot...

Organochlorine pesticides (OCPs) are persistent pollutants linked to diverse adverse health outcomes. Environmental exposure to OCPs has been suggested to negatively impact the immune system but their effects on cellular antiviral responses remain unknown. Transcriptomic analysis of N27 rat dopaminergic neuronal cells unexpectedly detected high lev...

Background: Acute intoxication caused by binge ethanol drinking is linked to widespread impairments in brain functions. Various alcohol administration paradigms have been used in animals to model the heterogenous clinical manifestation of intoxication in people. It is challenging to model a procedure that produces "visible intoxication" in rodents...

Background Microglia are the resident immune cells in the brain where they play essential roles in the development and maintenance of physiological functions of this organ. Aberrant activation of microglia is speculated to be involved in the pathogenesis of a variety of neurological disorders, including alcohol use disorders. Repeated binge ethanol...

Organochlorine pesticides, once widely used, are extremely persistent and bioaccumulative in the environment. Epidemiological studies have implicated that environmental exposure to organochlorine pesticides including dieldrin is a risk factor for the development of Parkinson’s disease. However, the pertinent mechanisms of action remain poorly under...

Microglia, the resident immune cells of the brain, can exhibit a broad range of activation phenotypes, many of which have been implicated in several diseases and disorders of the central nervous system including those related to alcohol abuse. Given the complexity of global-scale molecular changes that define microglial activation, accurate phenoty...

Microglia, as the resident brain immune cells, can exhibit a broad range of activation phenotypes, which have been implicated in a multitude of central nervous system disorders. Current widely studied microglial cell lines are mainly derived from neonatal rodent brain which can limit their relevance to homeostatic function and disease‐related neuro...

Environmental exposure to organochlorine pesticides (OCP) has been implicated as a risk factor for Parkinson's disease (PD), a devastating movement disorder characterized by massive loss of dopamine (DA) producing neurons in the substantia nigra and clinical symptoms including bradykinesia, rigidity and tremor. PD is the second most prevalent neuro...

Environmental exposure to the highly persistent chlorinated pesticides including dieldrin and lindane is postulated to be a risk factor to the development of Parkinson’s disease, a devastating movement disorder. We have previously reported that the combined treat-ment with dieldrin and lindane induces a cooperative toxicity in the rat N27 dopaminer...

Neuroinflammation, especially activation of microglia, the key immune cells in the brain, has been proposed to contribute to the pathogenesis of ischemic stroke. However, the dynamics and the potential mediators of microglial activation following ischemic neuronal injury are not well understood. In this study, using oxygen/glucose deprivation and r...

Stable isotope labeling by amino acids in cell culture (SILAC) is a versatile mass spectrometry-based proteomic approach that can achieve accurate relative protein quantitation on a global scale. In this approach, proteins are labeled while being synthesized by the cell due to the presence of certain amino acids exclusively as heavier mass analogs...

Microglia have increasingly been recognized as playing a wide spectrum of roles in various physiological and pathological processes in the central nervous system. Studies in the past have mostly associated individual microglial enzymes or soluble factors such as cytokines with specific functions of microglia. Stable isotope labeling with amino acid...

Microglia play important and dynamic roles in mediating a variety of physiological and pathological processes during the development, normal function and degeneration of the central nervous system. Application of SILAC-based proteomic analysis would greatly facilitate the identification of cellular pathways regulating the multifaceted phenotypes of...

Inflammation in the brain, that is, neuroinflammation, can be triggered by the presence of foreign substances including microbial pathogens and the occurrence of neuronal injury inflicted by ischemic, traumatic, and neurotoxic insults. This chapter summarizes the key features of cellular and molecular mediators of neuroinflammation and their releva...

Microglia, the resident immune cells of the brain, have been shown to display a complex spectrum of roles that span from neurotrophic to neurotoxic depending on their activation status. Microglia can be classified into four stages of activation, M1, which most closely matches the classical (pro-inflammatory) activation stage, and the alternative ac...

Long-term exposure to alcohol can have profound effects on the central nervous system including pathophysiological consequences associated with neuroinflammation. Along with astroglia, microglia play an important role in the neuroinflammatory response. Using a SILAC-labeled rat microglial cell line, an expression profile of 2,994 proteins was ident...

Exposure to excessive levels of manganese (Mn) is associated with the development of movement disorders with symptoms overlapping with Parkinson's disease. Oxidative damage has been implicated as a key contributor to Mn-induced neurotoxicity. We have recently reported that divalent Mn (Mn(2+)) stimulates brain microglia to produce and release hydro...

J. Neurochem. (2012) 122 , 752–763. Abstract Factors released from injured dopaminergic (DA) neurons may trigger microglial activation and set in motion a vicious cycle of neuronal injury and inflammation that fuels progressive DA neurodegeneration in Parkinson’s disease. In this study, using proteomic and immunoblotting analysis, we detected elev...

Ethanol exposure causes neurotoxicity, where neuroinflammation has been proposed to contribute to ethanol neurotoxicity. In addition to astroglia, microglia, as resident immune cells in the central nervous system, have been implicated as a key contributor to the neuroimmune and inflammatory processes. However, little is known regarding the role of...

Highly aggressively proliferating immortalized (HAPI) microglial cells have been used as an in vitro model for investigating key microglial functions including inflammatory, neurotoxic, and phagocytic activities. Through the use of offline strong cation-exchange fractionation followed by inline reversed-phase chromatographic separation and tandem m...

Elevated environmental exposure to pesticides has been implicated as a contributing factor in the pathogenesis of Parkinson's disease (PD), a progressive movement disorder resulted from degeneration of the nigrostriatal dopaminergic (DA) pathway. Organochlorine pesticides (OCPs) including dieldrin and lindane remain ubiquitous in the environment an...

Overexposure to manganese is known to cause damage to basal ganglial neurons and the development of movement abnormalities. Activation of microglia and astrocytes has increasingly been associated with the pathogenesis of a variety of neurological disorders. We have recently shown that microglial activation facilitates manganese chloride (MnCl2, 10-...

Exposure to elevated levels of manganese has been shown to cause neuronal damage in the midbrain and the development of Parkinsonian symptoms. Activation of microglia and release of neurotoxic factors in particular free radicals are known to contribute to neurodegeneration. We have recently reported that manganese chloride (MnCl(2)) stimulates micr...

Elevated environmental exposure to pesticides is a known risk factor to the development of sporadic Parkinson's disease resulting from the degeneration of nigral dopamine neurons. Among the suspected agents are the highly persistent and bioaccumulative organochlorinated pesticides (OCPs). We report here that lindane and dieldrin, two widely present...

Research in the last two decades has unveiled an important role for neuroinflammation in the degeneration of the nigrostriatal dopaminergic (DA) pathway that constitutes the pathological basis of the prevailing movement disorder, Parkinson's disease (PD). Neuroinflammation is characterized by the activation of brain glial cells, primarily microglia...

Exposure to pesticides has been speculated to contribute to the development of sporadic Parkinson's disease (PD) characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway. Activation of brain microglia that produce various neurotoxic factors including cytokines and reactive oxygen species (ROS) has been increasingly asso...

Elevated exposure to manganese is known to cause neurodegeneration in the basal ganglia and to induce movement abnormalities called manganism. However, the underlying mechanism of action is not fully understood. Activation of the resident immune cells in the brain, microglia that release a variety of neurotoxic factors, has been implicated to contr...

Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesi...

Parkinson's disease (PD) is a debilitating movement disorder resulting from a progressive degeneration of the nigrostriatal dopaminergic pathway and depletion of neurotransmitter dopamine in the striatum. Molecular cloning studies have identified nearly a dozen genes or loci that are associated with small clusters of mostly early onset and genetic...

Microglia are activated by lipopolysaccharide (LPS) to produce neurotoxic pro-inflammatory factors and reactive oxygen species (ROS). While a multitude of LPS receptors and corresponding pathways have been identified, the detailed mechanisms mediating the microglial response to LPS are unclear. Using mice lacking a functional toll-like receptor 4 (...

The importance of cyclooxygenase-2 (COX-2) in mediating Parkinson's disease (PD) was suggested in reports, indicating that COX-2 selective inhibitors or genetic knockout reduce 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neurotoxicity in a mouse model of PD. However, cell types and mechanisms underlying the activat...

The purpose of this study was to develop a novel therapy for Parkinson's disease (PD). We recently reported that dextromethorphan (DM), an active ingredient in a variety of widely used anticough remedies, protected dopaminergic neurons in rat primary mesencephalic neuron-glia cultures against lipopolysaccharide (LPS)-mediated degeneration and provi...

Accumulating evidence has suggested that inflammation in the brain participates in the pathogenesis of Parkinson's disease (PD). Therefore, anti-inflammatory therapy has attracted much attention as novel interference to neurodegenerative diseases. Baicalein, a major flavonoid extracted from a traditional Chinese herb Scutellaria baicalensis Georgi...

Dextromethorphan (DM) is a dextrorotatory morphinan and an over-the-counter non-opioid cough suppressant. We have previously shown that DM protects against LPS-induced dopaminergic neurodegeneration through inhibition of microglia activation. Here, we investigated protective effects of DM against endotoxin shock induced by lipopolysaccharide/d-gala...

Inflammation plays an important role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease. Recent reports have indicated that andrographolide (ANDRO) has an anti-inflammatory effect by modulating macrophage and neutrophil activity. Whereas microglia, the counterpart of macrophages in the brain, are pivotal in the...

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra and depletion of the neurotransmitter dopamine in the striatum. Progress in the search for effective therapeutic strategies that can halt this degenerative process remains limited. Mechanistic studies...

Reactive oxygen species (ROS) produced by activated microglia are deleterious to neurons. In this study, we studied the effect of Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), a superoxide dismutase/catalase mimetic, on the lipopolysaccharide (LPS)-induced degeneration of dopaminergic neurons in rat mesencephalic neuroglia cultures. MnTMP...

We determined the roles of reactive oxygen species (ROS) in the expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-activated microglia. LPS treatment increased intracellular ROS in rat microglia dose-dependently. Pre-treatment with superoxide dismutase (SOD)/catalase, or SOD/catalase mim...

Parkinson's disease (PD) is a profound movement disorder resulting from progressive degeneration of the nigrostriatal dopaminergic pathway. Although its etiology remains unknown, increasing evidence suggests the involvement of multiple factors such as environmental toxins and genetic susceptibilities in the pathogenesis of PD. In this study using m...

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons as seen in Parkinson's disease. Although increasing evidence suggests an involvement of glia in MPTP neurotoxicity, the nature of this involvement remains unclear. Exploiting the advantage of cell culture systems, we demonstrated that microglia, but not astroglia, sign...

Parkinson's disease (PD) is a movement disorder that is characterized by progressive degeneration of the nigrostriatal dopamine system. Although dopamine replacement can alleviate symptoms of the disorder, there is no proven therapy to halt the underlying progressive degeneration of dopamine-containing neurons. Recently, increasing evidence from hu...

Increasing evidence has suggested an important role for environmental toxins such as pesticides in the pathogenesis of Parkinson's disease (PD). Chronic exposure to rotenone, a common herbicide, reproduces features of Parkinsonism in rats. Mechanistically, rotenone-induced dopaminergic neurodegeneration has been associated with both its inhibition...

Idiopathic Parkinson's disease (PD) is a devastating movement disorder characterized by selective degeneration of the nigrostriatal dopaminergic pathway. Neurodegeneration usually starts in the fifth decade of life and progresses over 5-10 years before reaching the fully symptomatic disease state. Despite decades of intense research, the etiology o...

Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease. Inflammation-mediated neurodegeneration involves activation of the brain's resident immune cells, the microglia, which produce proinflammatory and neu...

Parkinson's disease (PD) is characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway resulting in movement disorders. Although its etiology remains unknown, PD may be the final outcome of interactions among multiple factors, including exposure to environmental toxins and the occurrence of inflammation in the brain. In t...

Degeneration of dopaminergic neurons in the substantia nigra is a hallmark of Parkinson’s disease (PD). However, despite decades of research, the cause of PD and the underlying mechanism of action responsible for the progressive degeneration of nigral dopaminergic neurons remain poorly understood (1). The creation of rodent and primate models for P...

Evidence from postmortem analysis implicates the involvement of microglia in the neurodegenerative process of several degenerative neurological diseases, including Alzheimer's disease and Parkinson's disease. It remains to be determined, however, whether microglial activation plays a role in the initiation stage of disease progression or occurs mer...

The purpose of this study was to assess and compare the toxicity of beta-amyloid (Abeta) on primary cortical and mesencephalic neurons cultured with and without microglia in order to determine the mechanism underlying microglia-mediated Abeta-induced neurotoxicity. Incubation of cortical or mesencephalic neuron-enriched and mixed neuron-glia cultur...

Previously we reported that naloxone stereoisomers, in an opioid receptor-independent manner, attenuated the inflammation-mediated degeneration of dopaminergic neurons by inhibition of the activation of microglia, the resident immune cells in the brain. Recently we discovered that beta-amyloid peptide Abeta (1-42) exhibited enhanced neurotoxicity t...

Cyclooxygenases (COX), key enzymes in prostanoid biosynthesis, may represent important therapeutic targets in various neurodegenerative diseases. In the present study, we explored the role of COX in Parkinson's disease (PD) by using 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine (MPTP) as a tool to create a rodent Parkinsonian model. MPTP (20 mg/kg...

The etiology of sporadic Parkinson's disease (PD) remains unknown. Increasing evidence has suggested a role for inflammation in the brain in the pathogenesis of PD. However, it has not been clearly demonstrated whether microglial activation, the most integral part of the brain inflammatory process, will result in a delayed and progressive degenerat...

Increasing evidence has suggested that inflammation in the brain is closely associated with the pathogenesis of several degenerative neurologic disorders, including Parkinson's disease, Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. The hallmark of brain inflammation is the activation of glial cells, esp...

Immune stimulants, such as the bacterial endotoxin, lipopolysaccharide (LPS), the human immunodeficiency virus-1 coat protein gp120, or beta-amyloid peptides, lead to glial activation and production of various immune mediators, such as nitric oxide (NO) and proinflammatory cytokines in the brain. These mediators appear to contribute to neuronal cel...

Increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in the pathogenesis of Parkinson's disease. In experimental animals the exposure to a common herbicide, rotenone, induces features of parkinsonism; mechanistically, rotenone-induced destruction of dopaminergic neurons has been attributed to...

Microglial responses to endotoxin, including the synthesis of inflammatory factors, contribute to gliosis and neuron degeneration in cultured brain tissue. We have previously shown that Gö6976, a protein kinase C (PKC) inhibitor, suppressed the lipopolysaccharide (LPS)-induced production of inflammatory factors in microglia and afforded marked prot...

The hallmark of Parkinson's disease is the death of nigral dopaminergic neurons, and inflammation in the brain has been increasingly associated with the pathogenesis of this neurological disorder. Dynorphins are among the major opioid peptides in the striato-nigral pathway and are important in regulating dopaminergic neuronal activities. However, i...

Ceramide accumulation in the cell can occur from either hydrolysis of sphingomyelin or by de novo synthesis. In this study, we found that blocking de novo ceramide synthesis significantly inhibits ceramide accumulation and subsequent cell death in response to tumor necrosis factor α. When cells were pre-treated with glutathione, a proposed cellular...

Microglia, the resident immune cells in the brain, play a pivotal role in immune surveillance, host defense, and tissue repair in the CNS. In response to immunological challenges, microglia readily become activated as characterized by morphological changes, expression of surface antigens, and production of immune modulators that impact on neurons t...

A massive degeneration of dopamine-containing neurons in the substantia nigra (SN) in the midbrain is characteristic of Parkinson's disease. Inflammation in the brain has long been speculated to play a role in the pathogenesis of this neurological disorder. Recently, we reported that treatment of primary rat mesencephalic mixed neuron-glia cultures...

Activation of glial cells often occurs at sites of neuronal injury or death and where there is disruption of communication between glia and neurons. We have previously reported that neurons exert an inhibitory influence on LPS-stimulated nitric oxide (NO) production in glial cells. We hypothesized that neural cell adhesion molecules (NCAM) might me...

Inflammation in the brain has been increasingly associated with the development of a number of neurological diseases. The hallmark of neuroinflammation is the activation of microglia, the resident brain immune cells. Injection of bacterial endotoxin lipopolysaccharide (LPS) into the hippocampus, cortex, or substantia nigra of adult rats produced ne...

Degeneration of dopaminergicrgic neurons in the substantia nigra of the brain is a hallmark of Parkinson's disease and inflammation and oxidative stress are closely associated with the pathogenesis of degenerative neurological disorders. Treatment of rat mesencephalic mixed neuron-glia cultures with lipopolysaccharide (LPS)-activated microglia, res...

An inflammatory response in the CNS mediated by activation of microglia is a key event in the early stages of the development of neurodegenerative diseases. Using mouse cortical mixed glia cultures, we have previously demonstrated that the bacterial endotoxin lipopolysaccharide induces the activation of microglia and the production of proinflammato...

A sudden increase in extracellular potassium ions (K⁺) often occurs in cerebral ischemia and after brain trauma. This increase of extracellular K⁺ constitutes the basis for spreading depression across the cerebral cortex, resulting in the expansion of neuronal death after ischemic and traumatic brain injuries. Besides spreading depression, it has b...

Ever since the initial discovery of ceramide-induced apoptosis, it has become critical to understand the cellular mechanisms responsible for the regulation of its biosynthesis. A major route of ceramide generation is the sphingomyelinase (SMase)-eatalyzed hydrolysis of cell membrane sphingomyelin (SM). Of the multiple forms of SMases discovered thu...

Ceramide is a product of membrane sphingolipid breakdown and has been proposed as an important mediator of apoptosis. A major source of ceramide is the hydrolysis of membrane sphingomyelin (SM) to generate ceramide and phosphorylcholine, a enzymatic reaction catalyzed by sphingomyelinase (SMase). To date, five types of SMases have been described, i...

Previously we reported that ultralow concentrations of dynorphins (10–16 to 10–12 M) inhibited lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and proinflammatory cytokines in mouse glia without the participation of -opioid receptors. In the current study using mouse cortical neuron-glia cocultures, we examined the possibility that...

Sphingomyelin hydrolysis and ceramide generation catalyzed by sphingomyelinases (SMase) are key components of the signaling pathways in cytokine- and stress-induced cellular responses. In this study, we report the partial purification and characterization of the membrane bound, neutral pH optimal, and magnesium-dependent SMase (N-SMase) from rat br...

Tumor necrosis factor-α (TNFα)-induced cell death involves a diverse array of mediators and regulators including proteases, reactive oxygen species, the sphingolipid ceramide, and Bcl-2. It is not known, however, if and how these components are connected. We have previously reported that GSH inhibits, in vitro, the neutral magnesium-dependent sphin...

Thioredoxin peroxidase (TPx) is a member of a newly discovered family of proteins that are conserved from yeast to mammals and to which natural killer enhancing factor belongs. These proteins are antioxidants that function as peroxidases only when coupled to a sulfhydryl reducing system. The physiological function of TPx in cells is not yet known....

The role of cytosolic phospholipase A2 (cPLA2) in the regulation of ceramide formation was examined in a cell line (L929) responsive to the cytotoxic action of tumor necrosis factor α (TNFα). In L929 cells, the addition of TNFα resulted in the release of arachidonate, which was followed by a prolonged accumulation of ceramide occurring over 5–12 h...

Sphingomyelin hydrolysis and ceramide generation have emerged as key events in cellular regulation. Sphingomyelinases (SMases) catalyse the breakdown of sphingomyelin to form ceramide and phosphorylcholine. Ceramide formed through activation of SMases may function as a second messenger in mediating cell growth, differentiation, stress responses, an...

Sphingomyelin hydrolysis through the activation of sphingomyelinases has become a potentially important signaling pathway with the product ceramide implicated in the regulation of cell growth, differentiation, apoptosis, and inflammatory responses. However, little is known about the regulation of sphingomyelinases. In this study, we show that the m...

Among its diverse biologic effects, the cytokine tumor necrosis factor alpha causes the rapid nuclear translocation of the transcription factor, nuclear factor kappaB (NF-kappaB). The p55 tumor necrosis factor (TNF) receptor shares with the related APO-1/Fas antigen the ability to initiate apoptosis. We investigated the role of the sphingolipid med...

The activation of sphingomyelinase and generation of ceramide have been implicated as important regulatory pathways in cell growth and apoptosis. Bacterial sphingomyelinase has been used in many cell systems to mimic the activation of endogenous sphingomyelinase. These studies, however, have been complicated by the inability of exogenously applied...

Prostate carcinoma has become the second most fatal cancer in American men. In rat Dunning prostate adenocarcinoma cells, increased cellular motility has been associated positively with their increased metastatic potential. However, the mechanism(s) responsible for regulation of tumor cell motility is poorly understood. We have reported that a lipo...

In B16a melanoma cells, protein kinase-C-alpha (PKC alpha) is immunomorphologically associated with cytoplasmic vesicles in addition to the previously observed locations (plasma membrane, cytoskeleton, nucleus), as detected with monoclonal antibody (MAb) MC3a. Subcellular fractionation indicated that the authentic 80-KD protein as well as PKC activ...

Protein kinase C (PKC) isoenzymes are essential components of cell signaling. In this study, we investigated the regulation of PKC-alpha in murine B16 amelanotic melanoma (B16a) cells by the monohydroxy fatty acids 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] and 13(S)-hydroxyoctadecadienoic acid [13(S)-HODE]. 12(S)-HETE induced a translocation...

Triggering of the Fas/APO-1 cell-surface receptor induces apoptosis through an uncharacterized chain of events. Exposure of Fas-sensitive cells to an agonist monoclonal antibody induced cell death and a 200-300% elevation in endogenous levels of the sphingolipid ceramide, a proposed intracellular mediator of apoptosis. In contrast, similar treatmen...

The dependence of some cell types on serum factors for growth may represent a powerful, but poorly studied, model for antimitogenic pathways. In this study, we examine ceramide as a candidate intracellular mediator of serum factor dependence. In Molt-4 leukemia cells, serum withdrawal caused a significant arrest in cell cycle progression (80% of ce...

Arachidonic acid metabolites have been implicated in multiple steps of carcinogenesis. Their role in tumor cell metastasis, the ultimate challenge for the treatment of cancer patients, are however not well-documented. Arachidonic acid is primarily metabolized through three pathways, i.e., cyclooxygenase, lipoxygenase, and P450-dependent monooxygena...

Low-dose gamma radiation stimulates expression of phenotypic characteristics in B16 melanoma cells which regulate metastatic potential. A transient increase in the expression of an integrin receptor (alpha IIb beta 3) was observed after exposure of B16 melanoma cells to 0.25 to 2.0 Gy of gamma radiation. This increased receptor expression resulted...

Prostate carcinoma has become the second most fatal cancer in American men. In Dunning R3327 rat prostate adenocarcinoma cells, elevated invasiveness positively correlates with metastatic potential. However, the mechanism(s) responsible for regulation of tumor cell motility and invasion is poorly understood. We have reported that a lipoxygenase met...

We have previously demonstrated that the metastatic potential of tumor cells can be increased by treatment with exogenous 12(S)hydroxyeicosatetraenoic acid [12(S)-HETE], a lipoxygenase metabolite of arachidonic acid. However, the biosynthesis of the authentic lipid mediator by tumor cells, and especially the correlation of its biosynthesis to tumor...

12(S)-Hydroxyeicosatetraenoic acid [12(S)-HETE] is the 12-lipoxygenase metabolite of arachidonic acid. Previously, we have demonstrated that exogenous 12(S)-HETE can activate protein kinase C, increase cell surface expression of integrins, enhance adhesion, induce endothelial cell retraction, and increase experimental metastasis of tumor cells. Bec...

Tumor cell — extracellular matrix interactions consist of attachment, spreading, migration and digestion of matrix ligands. These interactions are critical determinants during metastasis (1,2) and are mediated by receptors consisting of integrins, cell adhesion molecules (CAM) and proteoglycans (3,4). The first step in matrix interaction is a passi...

Protein kinase C (PKC), the Ca2+ and phospholipid dependent kinase, belongs to the family of protein serine/threorine kinases (1). It is an important enzyme in mediating cell growth, cell differentiation and tumor promotion (2,3). Physiologically, PKC is activated by diacylglycerol (DAG) generated during phosphatidylinositol (PI) turnover. Metaboli...

Prostaglandins and other eicosanoids have been studied extensively in their physical, biochemical, biophysical and pharmacological aspects. However, studies on their role in tumor progression, especially metastases are relatively recent. Following a brief overview of the history of discovery and metabolism of eicosanoids and other fatty acids, we d...

Tumor-cell interaction with the vessel wall during metastasis involves adhesion, induction of endothelial-cell retraction and spreading on the exposed sub-endothelial matrix. The signals for initiation of tumor-cell spreading and the receptors involved are unknown. A protocol was developed to distinguish between initial tumor-cell (B16 amelanotic m...

We recently reported that the Ca(2+)- and phospholipid-dependent protein kinase, protein kinase C (PKC), was involved in rat Walker carcinosarcoma cell adhesion to large-vessel endothelium. We extended our studies to explore the role of this kinase in the adhesion to small-vessel endothelium and lung colonization of murine B16 amelanotic melanoma (...

12(S)-hydroxyeicosatetraenoic acid (12[S]-HETE) and 13(S)-hydroxyoctadecadienoic acid (13[S]-HODE), lipoxygenase metabolites of arachidonic acid and linoleic acid, respectively, previously have been suggested to regulate tumor cell adhesion to endothelium during metastasis. Adhesion of rat Walker carcinosarcoma (W256) cells to a rat endothelial cel...