ABSTRACT
Oxic lake surface waters are frequently oversaturated with methane (CH4). The contribution to the global CH4 cycle is significant, thus leading to an increasing number of studies and stimulating debates. Here we show, using a mass balance, on a temperate, mesotrophic lake, that ~90% of CH4 emissions to the atmosphere is due to CH4 produced within the oxic surface mixed layer (SML) during the stratified period, while the often observed CH4 maximum at the thermocline represents only a physically driven accumulation. Negligible surface CH4 oxidation suggests that the produced 110 ± 60 nmol CH4 L-1 d-1 efficiently escapes to the atmosphere. Stable carbon isotope ratios indicate that CH4 in the SML is distinct from sedimentary CH4 production, suggesting alternative pathways and precursors. Our approach reveals CH4 production in the epilimnion that is currently overlooked, and that research on possible mechanisms behind the methane paradox should additionally focus on the lake surface layer.
ABSTRACT
The synthetic steroid mifepristone blocks the growth of ovarian cancer cells, yet the mechanism driving such effect is not entirely understood. Unbiased genomic and proteomic screenings using ovarian cancer cell lines of different genetic backgrounds and sensitivities to platinum led to the identification of two key genes upregulated by mifepristone and involved in the unfolded protein response (UPR): the master chaperone of the endoplasmic reticulum (ER), glucose regulated protein (GRP) of 78 kDa, and the CCAAT/enhancer binding protein homologous transcription factor (CHOP). GRP78 and CHOP were upregulated by mifepristone in ovarian cancer cells regardless of p53 status and platinum sensitivity. Further studies revealed that the three UPR-associated pathways, PERK, IRE1α, and ATF6, were activated by mifepristone. Also, the synthetic steroid acutely increased mRNA translation rate, which, if prevented, abrogated the splicing of XBP1 mRNA, a non-translatable readout of IRE1α activation. Moreover, mifepristone increased LC3-II levels due to increased autophagic flux. When the autophagic-lysosomal pathway was inhibited with chloroquine, mifepristone was lethal to the cells. Lastly, doses of proteasome inhibitors that are inadequate to block the activity of the proteasomes, caused cell death when combined with mifepristone; this phenotype was accompanied by accumulation of poly-ubiquitinated proteins denoting proteasome inhibition. The stimulation by mifepristone of ER stress and autophagic flux offers a therapeutic opportunity for utilizing this compound to sensitize ovarian cancer cells to proteasome or lysosome inhibitors.
Subject(s)
Autophagy/drug effects , Lysosomes/metabolism , Mifepristone/pharmacology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Proteasome Inhibitors/pharmacology , Protein Biosynthesis/drug effects , Unfolded Protein Response/drug effects , Activating Transcription Factor 4/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Chloroquine/pharmacology , Cinnamates/pharmacology , Endoplasmic Reticulum Chaperone BiP , Eukaryotic Initiation Factor-2/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lysosomes/drug effects , Platinum/pharmacology , Protein Biosynthesis/genetics , Puromycin/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/drug effects , Thiourea/analogs & derivatives , Thiourea/pharmacology , Tunicamycin/pharmacologyABSTRACT
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