The lysophospholipase D enzyme Gdpd3 is required to maintain chronic myelogenous leukaemia stem cells.

Although advanced lipidomics technology facilitates quantitation of intracellular lipid components, little is known about the regulation of lipid metabolism in cancer cells. Here, we show that disruption of the Gdpd3 gene encoding a lysophospholipase D enzyme significantly decreased self-renewal capacity in murine chronic myelogenous leukaemia (CML) stem cells in vivo. Sophisticated lipidomics analyses revealed that Gdpd3 deficiency reduced levels of certain lysophosphatidic acids (LPAs) and lipid mediators in CML cells. Loss of Gdpd3 also activated AKT/mTORC1 signalling and cell cycle progression while suppressing Foxo3a/ß-catenin interaction within CML stem cell nuclei. Strikingly, CML stem cells carrying a hypomorphic mutation of Lgr4/Gpr48, which encodes a leucine-rich repeat (LRR)-containing G-protein coupled receptor (GPCR) acting downstream of Gdpd3, displayed inadequate disease-initiating capacity in vivo. Our data showing that lysophospholipid metabolism is required for CML stem cell maintenance in vivo establish a new, biologically significant mechanism of cancer recurrence that is independent of oncogene addiction.

Survey of airborne polyfluorinated telomers in Keihan area, Japan.

Perfluorooctanoate (PFOA) are environmental contaminants posing special public health concerns because of their long-term persistence and bioaccumulation in the environment. Fluorotelomer alcohols are volatile and may undergo long-range transport. Air samples were collected at five sites in the Keihan area, Japan: Sakyo, Morinomiya and three sites in Higashiyodogawa. Except for Higashiyodogawa, the highest concentrations of fluorotelomer alcohols (FTOHs) were for 8:2 FTOH (median 447 pg m(-3)) followed by 10:2 FTOH (56 pg m(-3)) and 6:2 FTOH (22 pg m(-3)). In contrast, 8:2 FTOAcryl (median 865 pg m(-3)) and 8:2 FTOH (1,864 pg m(-3)) were both major components in Higashiyodogawa. Compared to data published for North America and Europe, 8:2 FTOH levels are significantly higher in Keihan, suggesting a possible point source.

Effects of perfluorooctane sulfonate on tracheal ciliary beating frequency in mice.

Perfluorooctane sulfonate (PFOS) is one of the emerging persistent organic pollutants, ubiquitously found in the global environment, even in human serum. PFOS has been reported to perturb Ca(2+) homeostasis in Paramecium, cardiomyocytes and neurons. Since ciliary beat frequency (CBF) in the trachea is known to be increased by cytoplasmic Ca(2+) elevation, the effects of PFOS on CBF were evaluated in a slice preparation using video-enhanced contrast microscopy. PFOS increased CBF by 11% (P<0.05) at 100 microM, while it did not do so at 30 microM. At 100 microM, it increased intracellular Ca(2+) concentration ([Ca(2+)](i)) in mouse tracheal ciliary cells. In Ca(2+)-free solution, PFOS at 100 microM failed to increase CBF (0.96-fold of vehicle control). The addition of Gd(3+) (1 microM), a store-operated Ca(2+) channel blocker, did not prevent the increase in CBF (1.09-fold (P<0.01) of vehicle control). High extracellular K(+) concentration (50 mM), which causes depolarization of the plasma membrane potential and a transient increase in [Ca(2+)](i), increased CBF by 20% (P<0.05). This observation indicates involvement of voltage-dependent Ca(2+) channels (VDCCs) in stimulation of CBF. Nifedipine (30 microM), a selective VDCC blocker, antagonized the effects of high K(+) (0.92-fold of high K(+) solution) and PFOS (0.96-fold of vehicle control) on CBF. In cells from peroxisome proliferator-activated receptor alpha (PPARalpha)-null mice, PFOS still increased CBF (1.12-fold (P<0.05) of vehicle control), indicating that the actions of PFOS are not mediated via PPARalpha. These findings collectively suggest that PFOS stimulates CBF by increasing cytoplasmic Ca(2+) through VDCC.

Effects of perfluorinated amphiphiles on backward swimming in Paramecium caudatum.

PFOS and PFOA are ubiquitous contaminants in the environment. We investigated the effects of fluorochemicals on calcium currents in Paramecium caudatum using its behavioral changes. Negatively charged amphiphiles prolonged backward swimming (BWS) of Paramecium. PFOS significantly prolonged BWS, while PFOA was less potent (EC(50): 29.8+/-4.1 and 424.1+/-124.0microM, respectively). The BWS prolongation was blocked by cadmium, indicating that the cellular calcium conductance had been modified. The positively charged amphiphile FOSAPrTMA shortened BWS (EC(50): 19.1+/-17.3). Nonionic amphiphiles did not affect BWS. The longer-chain perfluorinated carboxylates PFNA and PFDA were more potent than PFOA (EC(50): 98.7+/-20.1 and 60.4+/-10.1microM, respectively). However, 1,8-perfluorooctanedioic acid and 1,10-perfluorodecanedioic acid did not prolong BWS. The critical micelle concentration (CMC) and BWS prolongation for negatively charged amphiphiles showed a clear correlation (r(2)=0.8008, p<0.001). In summary, several perfluorochemicals and PFOS and PFOA had similar effects in Paramecium, while chain length, CMC, and electric charge were major determinants of BWS duration.