An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury

This article is free to read from PMC (see link below) We hypothesized that normal human mesothelial cells acquire resistance to asbestos-induced toxicity via induction of one or more epidermal growth factor receptor (EGFR) - linked survival pathways (phosphoinositol-3-kinase/AKT/ mammalian target of rapamycin and extracellular signal - regulated kinase [ERK] 1/2) during simian virus 40 (SV40) transformation and carcinogenesis. Both isolated HKNM-2 mesothelial cells and a telomerase-immortalized mesothelial line (LP9/TERT-1) were more sensitive to crocidolite asbestos toxicity than an SV40 Tag-immortalized mesothelial line (MET5A) and malignant mesothelioma cell lines (HMESO and PPM Mill). Whereas increases in phosphorylation of AKT (pAKT) were observed in MET5A cells in response to asbestos, LP9/TERT-1 cells exhibited dose-related decreases in pAKT levels. Pretreatment with an EGFR phosphorylation or mitogen-activated protein kinase kinase 1/2 inhibitor abrogated asbestos-induced phosphorylated ERK (pERK) 1/2 levels in both LP9/TERT-1 and MET5A cells as well as increases in pAKT levels in MET5A cells. Transient transfection of small interfering RNAs targeting ERK1, ERK2, or AKT revealed that ERK1/2 pathways were involved in cell death by asbestos in both cell lines. Asbestos-resistant HMESO or PPM Mill cells with high endogenous levels of ERKs or AKT did not show dose-responsive increases in pERK1/ERK1, pERK2/ERK2, or pAKT/AKT levels by asbestos. However, small hairpin ERK2 stable cell lines created from both malignant mesothelioma lines were more sensitive to asbestos toxicity than shERK1 and shControl lines, and exhibited unique, tumor-specific changes in endogenous cell death - related gene expression. Our results suggest that EGFR phosphorylation is causally linkedto pERK and pAKT activation by asbestos in normal and SV40 Tag - immortalized human mesothelial cells. They also indicate that ERK2 plays a role in modulating asbestos toxicity by regulating genes critical to cell injury and survival that are differentially expressed in human mesotheliomas

QCD Coherence and correlations of particles with restricted momenta in hadronic Z decays.

QCD coherence effects are studied based on measurements of correlations of particles with either restricted transverse momenta, pT<pTcut, where pT is defined with respect to the thrust axis, or restricted absolute momenta, p equiv |p| < pcut, using about four million hadronic Z decays recorded at LEP with the OPAL detector. The correlations are analyzed in terms of normalized factorial and cumulant moments. The analysis is inspired by analytical QCD calculations which, in conjunction with Local Parton-Hadron Duality (LPHD), predict that, due to colour coherence, the multiplicity distribution of particles with restricted transverse momenta should become Poissonian as pTcut decreases. The expected correlation pattern is indeed observed down to pTcut approx 1GeV but not at lower transverse momenta. Furthermore, for pcut to 0 GeV a strong rise is observed in the data, in disagreement with theoretical expectation. The Monte Carlo models reproduce well the measurements at large pTcut and pcut but underestimate their magnitudes at the lowest momenta. The e+e- data are also compared to the measurements in deep-inelastic e+p collisions. Our study indicates difficulties with the LPHD hypothesis when applied to many-particle inclusive observables of soft hadrons.Comment: 17 pages, 4 figures, Submitted to Phys. Letts.