Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid.

Cyclic phosphatidic acid (1-acyl-2,3-cyclic-glycerophosphate, CPA), one of nature's simplest phospholipids, is found in cells from slime mold to humans and has a largely unknown function. We find here that CPA is generated in mammalian cells in a stimulus-coupled manner by phospholipase D2 (PLD2) and binds to and inhibits the nuclear hormone receptor PPARgamma with nanomolar affinity and high specificity through stabilizing its interaction with the corepressor SMRT. CPA production inhibits the PPARgamma target-gene transcription that normally drives adipocytic differentiation of 3T3-L1 cells, lipid accumulation in RAW264.7 cells and primary mouse macrophages, and arterial wall remodeling in a rat model in vivo. Inhibition of PLD2 by shRNA, a dominant-negative mutant, or a small molecule inhibitor blocks CPA production and relieves PPARgamma inhibition. We conclude that CPA is a second messenger and a physiological inhibitor of PPARgamma, revealing that PPARgamma is regulated by endogenous agonists as well as by antagonists.

Controlling cancer through the autotaxin-lysophosphatidic acid receptor axis.

LPA (lysophosphatidic acid, 1-acyl-2-hydroxy-sn-glycero-3-phosphate), is a growth factor-like lipid mediator that regulates many cellular functions, many of which are unique to malignantly transformed cells. The simple chemical structure of LPA and its profound effects in cancer cells has attracted the attention of the cancer therapeutics field and drives the development of therapeutics based on the LPA scaffold. In biological fluids, LPA is generated by ATX (autotaxin), a lysophospholipase D that cleaves the choline/serine headgroup from lysophosphatidylcholine and lysophosphatidylserine to generate LPA. In the present article, we review some of the key findings that make the ATX-LPA signalling axis an emerging target for cancer therapy.

Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid.

Cyclic phosphatidic acid (1-acyl-sn-glycerol-2,3-cyclic phosphate; cPA) is a naturally occurring analog of lysophosphatidic acid (LPA) with a variety of distinctly different biological activities from those of LPA. In contrast to LPA, a potent inducer of tumor cell invasion, palmitoyl-cPA inhibits FBS- and LPA-induced transcellular migration and metastasis. To prevent the conversion of cPA to LPA we synthesized cPA derivatives by stabilizing the cyclic phosphate ring; to prevent the cleavage of the fatty acid we generated alkyl ether analogs of cPA. Both sets of compounds were tested for inhibitory activity on transcellular tumor cell migration. Carba derivatives, in which the phosphate oxygen was replaced with a methylene group at either the sn-2 or the sn-3 position, showed much more potent inhibitory effects on MM1 tumor cell transcellular migration and the pulmonary metastasis of B16-F0 melanoma than the natural pal-cPA. The antimetastatic effect of carba-cPA was accompanied by the inhibition of RhoA activation and was not due to inhibition of the activation of LPA receptors.

Biological functions of a novel lipid mediator, cyclic phosphatidic acid.

A novel bioactive lipid, cyclic phosphatidic acid (cPA), was isolated originally from myxoamoebae of a true slime mold, Physarum polycephalum, and has now been detected in a wide range of organisms from slime molds to humans. It has a cyclic phosphate at the sn-2 and sn-3 positions of the glycerol carbons, and this structure is absolutely necessary for its activities. This substance shows specific biological functions, including antimitogenic regulation of the cell cycle, regulation of actin stress fiber formation and rearrangement, inhibition of cancer cell invasion and metastasis, regulation of differentiation and viability of neuronal cells, and mobilization of intracellular calcium. Although the structure of cPA is similar to that of lysophosphatidic acid (LPA), its biological activities are apparently distinct from those of LPA. In the present review, we focus mainly on the enzymatic formation of cPA, the antimitogenic regulation of the cell cycle, the inhibition of cancer cell invasion and metastasis, and the neurotrophic effect of cPA.

Effect on mental health of a participatory intervention to improve psychosocial work environment: a cluster randomized controlled trial among nurses.

OBJECTIVES: Improvement of psychosocial work environment has proved to be valuable for workers' mental health. However, limited evidence is available for the effectiveness of participatory interventions. The purpose of this study was to investigate the effect on mental health among nurses of a participatory intervention to improve the psychosocial work environment. METHODS: A cluster randomized controlled trial was conducted in hospital settings. A total of 434 nurses in 24 units were randomly allocated to 11 intervention units (n=183) and 13 control units (n=218). A participatory program was provided to the intervention units for 6 months. Depressive symptoms as mental health status and psychosocial work environment, assessed by the Job Content Questionnaire, the Effort-Reward Imbalance Questionnaire, and the Quality Work Competence questionnaire, were measured before and immediately after the 6-month intervention by a self-administered questionnaire. RESULTS: No significant intervention effect was observed for mental health status. However, significant intervention effects were observed in psychosocial work environment aspects, such as Coworker Support (p<0.01) and Goals (p<0.01), and borderline significance was observed for Job Control (p<0.10). CONCLUSIONS: It is suggested that a 6-month participatory intervention is effective in improving psychosocial work environment, but not mental health, among Japanese nurses.

Association of social skills with psychological distress among female nurses in Japan.

Nursing is a highly stressful occupation. Because nursing work involves interaction with patients and colleagues, competence in social skills may be a key issue in stress management among nurses. However, there are very few studies among nurses focused on social skills together with social support, both of which are important aspects of job stress. The aim of this study was to examine the interrelationships between social skills and social support with job stressors, problem-solving coping, and psychological distress among Japanese nurses. Data from a self-administered questionnaire of 1,197 female nurses who worked for 5 general hospitals in Japan were analyzed. Covariance structure analysis with structural equation modeling techniques showed that social skills and social support were positively related to each other, while they were negatively associated with psychological distress and job stressors, and positively associated with problem-solving coping. Furthermore, the direct association between social skills and psychological distress was stronger than the association between social support and psychological distress. These findings suggested that improving not only social support at work but also individual social skills is important for nurses' mental health.

Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis.

Autotaxin (ATX, nucleotide pyrophosphate/phosphodiesterase-2) is an autocrine motility factor initially characterized from A2058 melanoma cell-conditioned medium. ATX is known to contribute to cancer cell survival, growth, and invasion. Recently ATX was shown to be responsible for the lysophospholipase D activity that generates lysophosphatidic acid (LPA). Production of LPA is sufficient to explain the effects of ATX on tumor cells. Cyclic phosphatidic acid (cPA) is a naturally occurring analog of LPA in which the sn-2 hydroxy group forms a 5-membered ring with the sn-3 phosphate. Cellular responses to cPA generally oppose those of LPA despite activation of apparently overlapping receptor populations, suggesting that cPA also activates cellular targets distinct from LPA receptors. cPA has previously been shown to inhibit tumor cell invasion in vitro and cancer cell metastasis in vivo. However, the mechanism governing this effect remains unresolved. Here we show that 3-carba analogs of cPA lack significant agonist activity at LPA receptors yet are potent inhibitors of ATX activity, LPA production, and A2058 melanoma cell invasion in vitro and B16F10 melanoma cell metastasis in vivo.

Steryl glucoside is a lipid mediator in stress-responsive signal transduction.

We previously reported that steryl glucoside (SG) is rapidly induced in cells from molds to humans by exposure to environmental stress (Murakami-Murofushi et al. (1997) J. Biol. Chem., 272, 486-489, Kunimoto et al. (2000) Cell Stress & Chaperones, 5, 3-7), and in mold cells SG production is followed by activation of a certain protein kinase and induction of heat shock proteins (HSP) (Maruya et al. (1997) Cell Struct. Funct., 21, 533-538). To determine the biological significance of SG in stress responsive signal transduction, we added SG to the culture of human fibroblasts and examined its effect on HSP induction. We demonstrated a rapid activation of heat shock transcription factor 1 (HSF1) to bind to heat shock element (HSE) and induction of heat shock protein 70 (HSP70) in fibroblast cells by exposure to exogenously added human major SG, cholesteryl glucoside (CG). In addition, enzyme activity to form CG from cholesterol and UDP-glucose was detected in the homogenate of fibroblast cells. These results strongly suggest that CG acts as a mediator in the early stage of stress responsive signal transduction.