Activation of PPARγ in myeloid cells promotes lung cancer progression and metastasis

PPARγ activators inhibit cancer cell growth. However the role of these agents in progression/metastasis is not well-defined. Using an orthotopic model of lung cancer, we showed that pioglitazone accelerated progression/metastasis through affects on macrophages. This suggests that potential therapeutic agents may have opposing effects on cancer in different cells

Peroxisome Proliferator-Activated Receptor-γ in Lung Cancer: Defining Specific Versus “Off-Target― Effectors

AbstractA large number of studies have indicated that thiazolidinediones (TZDs) such as rosiglitazone and pioglitazone inhibit tumor growth, progression, and metastasis. These agents are specific agonists for the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) but also engage other pathways. In lung cancer, these agents have been shown to induce apoptosis and inhibit tumor growth in xenograft models. Retrospective studies have indicated a significant decrease in lung cancer risk in patients using these agents, suggesting that TZDs may be chemopreventive for lung cancer. However, emerging data suggest that chronic use of these agents is associated with increased risk of adverse cardiovascular events. It is therefore critical to determine the relative contributions of PPARγ-dependent versus PPARγ-independent pathways in mediating both the anti-tumorigenic effects and the cardiovascular effects of TZDs. This review examines these pathways with a specific focus on the role of TZDs and PPARγ in lung cancer

You mean I can get paid to work here? The impact of happenstance, socialization, volunteering, and service-learning on nonprofit career awareness

Title from PDF of title page, viewed on July 24, 2013Dissertation advisor: Robert D. HermanVitaIncludes bibliographic references (pages 151-166)Thesis (Ph.D.)--Henry W. Bloch School of Management and Social Science Consortium. University of Missouri--Kansas City, 2013It is important to learn why workers choose to enter the nonprofit workforce over the public or private sectors. Doing so will allow nonprofit organizations to better target potential populations of candidates in their recruitment efforts, which will ensure that an adequate number of nonprofit professionals are being trained to fulfill future positions of nonprofit leadership. This dissertation will outline ways to understand the backgrounds of those who work in the nonprofit sector. The leadership deficit in nonprofit organizations is growing nearer. Over the next decade, a significant number of new nonprofit managers will be needed in the nonprofit sector to cover the retirement of the baby boomers, as well as the overall increase in number of nonprofits. Knowing key populations for recruitment will allow nonprofits to more effectively and efficiently address their impending staffing needs. This research will utilize cross-sectional research approach to address what particular experiences nonprofit employees had prior to their entry into the sector that may have led to their entry into the nonprofit workforce. Research participants are from the membership of a national nonprofit organization dedicated to supporting individuals new to careers in the nonprofit sector. Research questions include whether nonprofit careers tend to be the product of intentional choice, or a matter of “right place, right time”, and whether various levels of engagement in service learning, socialization to the sector, and volunteering activities contribute to eventual employment in the nonprofit sector by allowing that population to see the sector as one that provides a viable career in their field.Introduction -- Review of literature -- Research design and methodology -- Results -- Discussion and conclusions -- Appendix A. List of missing values by variable -- Appendix B. Survey information letter -- Appendix C. Survey instrumen

Activation and Molecular Targets of Peroxisome Proliferator-Activated Receptor-γ Ligands in Lung Cancer

Lung cancer is the leading cause of cancer death, and five-year survival remains poor, raising the urgency for new treatment strategies. Activation of PPARγ represents a potential target for both the treatment and prevention of lung cancer. Numerous studies have examined the effect of thiazolidinediones such as rosiglitazone and pioglitazone on lung cancer cells in vitro and in xenograft models. These studies indicate that activation of PPARγ inhibits cancer cell proliferation as well as invasiveness and metastasis. While activation of PPARγ can occur by direct binding of pharmacological ligands to the molecule, emerging data indicate that PPARγ activation can occur through engagement of other signal transduction pathways, including Wnt signaling and prostaglandin production. Data, both from preclinical models and retrospective clinical studies, indicate that activation of PPARγ may represent an attractive chemopreventive strategy. This article reviews the existing biological and mechanistic experiments focusing on the role of PPARγ in lung cancer, focusing specifically on nonsmall cell lung cancer

Anti- and Protumorigenic Effects of PPAR γ

Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that plays an important role in the control of gene expression linked to a variety of physiological processes, including cancer. Ligands for PPARγ include naturally occurring fatty acids and the thiazolidinedione class of antidiabetic drugs. Activation of PPARγ in a variety of cancer cells leads to inhibition of growth, decreased invasiveness, reduced production of proinflammatory cytokines, and promotion of a more differentiated phenotype. However, systemic activation of PPARγ has been reported to be protumorigenic in some in vitro systems and in vivo models. Here, we review the available data that implicate PPARγ in lung carcinogenesis and highlight the challenges of targeting PPARγ in lung cancer treatments

Activation of cytosolic phospholipase A2 in dorsal root ganglion neurons by Ca2+/calmodulin-dependent protein kinase II after peripheral nerve injury

<p>Abstract</p> <p>Background</p> <p>Peripheral nerve injury leads to a persistent neuropathic pain state in which innocuous stimulation elicits pain behavior (tactile allodynia), but the underlying mechanisms have remained largely unknown. We have previously shown that spinal nerve injury induces the activation of cytosolic phospholipase A₂(cPLA₂) in injured dorsal root ganglion (DRG) neurons that contribute to tactile allodynia. However, little is known about the signaling pathway that activates cPLA₂after nerve injury. In the present study, we sought to determine the mechanisms underlying cPLA₂activation in injured DRG neurons in an animal model of neuropathic pain, focusing on mitogen-activated protein kinases (MAPKs) and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII).</p> <p>Results</p> <p>Pharmacological inhibition of either p38 or extracellular signal-regulated kinase (ERK) in the injured DRG, which led to suppression of the development of tactile allodynia, did not affect cPLA₂phosphorylation and translocation after nerve injury. By contrast, a CaMKII inhibitor prevented the development and expression of nerve injury-induced tactile allodynia and reduced both the level of cPLA₂phosphorylation and the number of DRG neurons showing translocated cPLA₂in response to nerve injury. Applying ATP to cultured DRG neurons increased the level of both phosphorylated cPLA₂and CaMKII in the vicinity of the plasma membrane and caused physical association of these two proteins. In addition, ATP-stimulated cPLA₂and CaMKII phosphorylation were inhibited by both a selective P2X₃R/P2X₂₊₃R antagonist and a nonselective voltage-dependent Ca²⁺channel (VDCC) blocker.</p> <p>Conclusion</p> <p>These results suggest that CaMKII, but not MAPKs, has an important role in cPLA₂activation following peripheral nerve injury, probably through P2X₃R/P2X₂₊₃R and VDCCs in primary afferent neurons.</p

Effect of glycine on prelethal and postlethal increases in calpain activity in rat renal proximal tubules

Effect of glycine on prelethal and postlethal increases in calpain activity in rat renal proximal tubules. The effect of glycine on hypoxia- and ionomycin-induced increases in calpain activity in rat proximal tubules was determined. Calpain activity was determined both in vitro and in the intact cell using the fluorescent substrate N-succinyl-Leu-Leu-Val-Tyr-7- amido-4-methyl coumarin (N-succinyl-Leu-Leu-Val-Tyr-AMC) and Western blotting for calpain-specific spectrin breakdown products (BDP), respectively. At 7.5 minutes of hypoxia (prelethal injury model) there was a significant (10-fold) increase in in vitro calpain activity that was not inhibited by glycine. At 15 minutes of hypoxia (postlethal injury model) there was a further increase in calpain activity that was inhibited by glycine. Normoxic tubules incubated with the calcium ionophore ionomy-cin (5 µM) for two minutes and 10 minutes had a significant increase in calpain activity that was not inhibited by glycine. After 15 minutes of hypoxia in the presence of glycine, there was an increase in calpain-specific spectrin breakdown products (BDP) in both Triton X-100 soluble and cytosolic extracts from proximal tubules. Glycine in concentrations up to 10mM had no direct effect on the in vitro calpain activity of purified calpains. The present study demonstrates that: (1) prelethal increases in calpain activity stimulated by hypoxia and ionomycin treatment are not affected by glycine; (2) calpain-mediated spectrin breakdown during hypoxia occurs in the presence of glycine; (3) glycine does prevent the additional postlethal increase in calpain activity probably by maintaining membrane integrity to calcium influx

Effect of nitric oxide donors on renal tubular epithelial cell-matrix adhesion

Effect of nitric oxide donors on renal tubular epithelial cell-matrix adhesion.BackgroundNitric oxide (NO) and its metabolite, peroxynitrite (ONOO-), are involved in renal tubular cell injury. We postulated that if NO/ONOO- has an effect to reduce cell adhesion to the basement membrane, this may contribute to tubular obstruction and may be partially responsible for the harmful effect of NO on the tubular epithelium during acute renal failure (ARF).MethodsWe examined the effect of the NO donors (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO), spermine NONOate (SpNO), and the ONOO- donor 3-morpholinosydnonimine (SIN-1) on cell-matrix adhesion to collagen types I and IV and fibronectin using three renal tubular epithelial cell lines: LLC-PK1, BSC-1, and OK.ResultsIn LLC-PK1 cells, DETA/NO (500 μm) had no effect, and SpNO (500 μm) had a modest effect on cell adhesion compared with controls. Exposure to SIN-1 caused a dose-dependent impairment in cell-matrix adhesion. Similar results were obtained in the different cell types and matrix proteins. The effect of SIN-1 (500 μm) on LLC-PK1 cell adhesion was not associated with either cell death or alteration of matrix protein and was attenuated by either the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, the superoxide scavenger superoxide dismutase, or the ONOO- scavenger uric acid in a dose-dependent manner.ConclusionsThese results therefore support the possibility that ONOO- generated in the tubular epithelium during ischemia/reperfusion has the potential to impair the adhesion properties of tubular cells, which then may contribute to the tubular obstruction in ARF

Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition–mediated cell death in K-ras mutant lung cancer cells

ObjectiveThere are currently no targeted therapies against lung tumors with oncogenic K-ras mutations that are found in 25% to -40% of lung cancers and are characterized by their resistance to epidermal growth factor receptor inhibitors. The isozyme group IIa secretory phospholipase A2 (sPLA2IIa) is a potential biomarker and regulator of lung cancer cell invasion; however, the relationship between K-ras mutations and sPLA2IIa has yet to be investigated. We hypothesize that sPLA2IIa modulates lung cancer cell growth in K-ras mutant cells and that sPLA2IIa expression in human lung tumors is increased in K-ras mutant tumors.MethodsBaseline sPLA2IIa expression in K-ras mutant lung cancer cell lines (A549, SW1573, H358, H2009) was assessed. Cells were treated with a specific sPLA2IIa inhibitor and evaluated for apoptosis and cell viability. Nuclear factor kappa-b (NF-κB) and extracellular signal-regulated kinase 1/2 activity were detected by Western blot. Human tumor samples were evaluated for sPLA2IIa mRNA expression by quantitative reverse-transcription polymerase chain reaction.ResultsCytotoxicity of sPLA2IIa inhibition correlates with sPLA2IIa expression. Apoptosis in response to sPLA2 inhibition parallels attenuation in NF-κB activity. In addition, sPLA2IIa expression in human tumors correlates with squamous cell pathology and increasing stage of K-ras mutant lung tumors.ConclusionsBaseline sPLA2IIa expression predicts response to sPLA2IIa inhibition in some K-ras mutant lung cancer cells. This finding is independent of p53 mutation status. Furthermore, squamous tumors and advanced-stage K-ras mutant tumors express more sPLA2IIa. These data support a role for sPLA2IIa as a potential global therapeutic target in the treatment of lung cancer