作者: Freeman, Michael R ; Freedland, Stephen J ; Zhang, Baohui ; Campbell, Moray J ; Garraway, Isla P ; Posadas, Edwin M ; You, Sungyong ; Yang, Wei ; Qian, Chen ; Yang, Qian ; Ellis, Leigh ; Mostaghel, Elahe A ; Morrissey, Colm ; Gallent, Brad ; Vizio, Dolores Di ; Knudsen, Beatrice S ; Nelson, Peter S ; Huang, Rongrong ; Rotinen, Mirja ; Kaochar, Salma ; Yan, Yiwu ; Cadaneanu, Radu M ; Murali, Ramachandran ; Brady, Lauren ; Kim, Hyoyoung ; Ye, Huihui

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor and the NE splicing factor SRRM4, among others. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. OC2 also activates glucuronidation genes that irreversibly disable androgen, thereby evoking phenotypic heterogeneity indirectly by hormone depletion. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC. Our findings support enhanced efforts to therapeutically target this protein as a means of suppressing treatment-resistant disease.

2022-10-01·Food and Chemical Toxicology

Triphenyltin(IV) dithiocarbamate compound induces genotoxicity and cytotoxicity in K562 human erythroleukemia cells primarily via mitochondria-mediated apoptosis

Article

作者: Syed Annuar, Sharifah Nadhira ; Awang, Normah ; Chan, Kok Meng ; Kamaludin, Nurul Farahana

The novel di-and triphenyltin(IV) dithiocarbamate compounds represented as R_nSnL₂ (where R = C₄H₉, C₆H₅; n = 2,3; L = N,N-dithiocarbamate), Ph₂Sn(N,N-diisopropyldithiocarbamate) (OC1), Ph₃Sn(N,N-diisopropyldithiocarbamate) (OC2), Ph₂Sn(N,N-diallyldithiocarbamate) (OC3), Ph₃Sn(N,N-diallyldithiocarbamate) (OC4), and Ph₂Sn(N,N-diethyldithiocarbamate) (OC5) were assessed for their cytotoxicity in K562 human erythroleukemia cells. All compounds inhibited the growth of cells at low micromolar concentrations (<10 μM), and the mechanism underlying their antiproliferative effects on K562 cells was apoptosis, as corroborated by the exposure of plasma membrane phosphatidylserine. OC2, which showed the most promising antiproliferative activity, was selected for further analyses. The results demonstrated that OC2 induced apoptosis in K562 cells via an intrinsic mitochondrial pathway triggered upon DNA damage, an early apoptotic signal. Subsequently, OC2 produced excessive intracellular reactive oxygen species. The role of oxidative stress was corroborated by the significant reduction in GSH levels and percentage of apoptosis in NAC-pretreated cells. OC2 could arrest the cell cycle progression in the S phase. These new findings elucidate the antiproliferative potential of OC2 in the K562 human erythroleukemia cells and warrant further investigation, specifically to determine the exact signaling pathway underlying its antileukemic efficacy.

2020-09-01·Environmental Science & Technology1区 · 环境科学与生态学

Changing Nature of Organic Carbon over the United States

1区 · 环境科学与生态学

Article

作者: Porter, William C. ; Christiansen, Amy E. ; Carlton, Annmarie G.

Total organic carbon (TOC) mass concentrations are decreasing across the contiguous United States (CONUS). We investigate decadal trends in organic carbon (OC) thermal fractions [OC1 (volatilizes at 140 °C), OC2 (280 °C), OC3 (480 °C), OC4 (580 °C)] and pyrolyzed carbon (PC), reported at 121 locations in the Interagency Monitoring of Protected Visual Environments (IMPROVE) network from 2005 to 2015 for 23 regions across the CONUS. Reductions in PC and OC2 drive decreases in TOC (TOC = OC1 + OC2 + OC3 + OC4 + PC) mass concentrations. OC2 decreases by 40% from 2005 to 2015, and PC decreases by 34%. The largest absolute mass decreases occur in the eastern United States, and relative changes normalized to local concentrations are more uniform across the CONUS. OC is converted to organic mass (OM) using region- and season-specific OM:OC ratios. Simulations with GEOS-Chem reproduce OM trends and suggest that decreases across the CONUS are due to aerosol liquid water (ALW) chemistry. Individual model species, notably aerosol derived from isoprene oxidation products and formed in ALW, correlate significantly (p < 0.05) with OM2, even in arid regions. These findings contribute to literature that suggests air quality rules aimed at SO₂ and NO_x emissions induce the cobenefit of reducing organic particle mass through ALW chemistry, and these benefits extend beyond the eastern United States.

100 项与 OC-2 相关的药物交易

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