MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors

There is increasing evidence that oncogenic transformation modifies the metabolic program of cells. A common alteration is the upregulation of glycolysis, and efforts to target glycolytic enzymes for anticancer therapy are under way. Here, we performed a genome-wide haploid genetic screen to identify resistance mechanisms to 3-bromopyruvate (3-BrPA), a drug candidate that inhibits glycolysis in a poorly understood fashion. We identified the SLC16A1 gene product, MCT1, as the main determinant of 3-BrPA sensitivity. MCT1 is necessary and sufficient for 3-BrPA uptake by cancer cells. Additionally, SLC16A1 mRNA levels are the best predictor of 3-BrPA sensitivity and are most elevated in glycolytic cancer cells. Furthermore, forced MCT1 expression in 3-BrPA–resistant cancer cells sensitizes tumor xenografts to 3-BrPA treatment in vivo. Our results identify a potential biomarker for 3-BrPA sensitivity and provide proof of concept that the selectivity of cancer-expressed transporters can be exploited for delivering toxic molecules to tumors.National Institutes of Health (U.S.) (NIH CA103866)Jane Coffin Childs Memorial Fund for Medical Research (Fellowship)National Science Foundation (U.S.) (Fellowship)Howard Hughes Medical Institute (Investigator

OsICE1 transcription factor improves photosynthetic performance and reduces grain losses in rice plants subjected to drought

Drought is a major environmental threat to agriculture sustainability. We have characterised the role of OsICE1, a basic helix-loop-helix (bHLH) transcription factor from rice (Oryza sativa L.), in response to drought. OsICE1 gene is constitutively expressed in roots and shoots of rice seedlings grown under control conditions, as well as in response to low temperature, high salinity, and ABA. Nevertheless, in response to drought, OsICE1 is up-regulated in roots. Plants over-expressing OsICE1 (OsICE1-OX) show improved drought tolerance at both vegetative and reproductive stages, whereas OsICE1 silenced plants (OsICE1-RNAi) show decreased drought tolerance in the same phenological stages. Under drought, OsICE1-OX plants show improved net photosynthetic rates and stomatal conductance to water vapour, as well as higher photochemical efficiency of photosystem II and tolerance to photo-inhibition, as compared to the WT and OsICE1-RNAi. In addition, under severe drought, OsICE1-OX plants show lower grain yield losses than WT, while OsICE1-RNAi plants show the highest grain losses. OsICE1-OX and OsICE1-RNAi plants do not differentially respond to ABA, and drought-inducible genes are more responsive in OsICE1-RNAi and less in OsICE1-OX plants (as compared to WT), suggesting that OsICE1 has a central role modulating molecular responses to drought in an ABA-independent way. This role might be mediated by OsWsi18, a LEA encoding gene up regulated in OsICE1-OX rice plants and known to enhance membrane stability under drought

Role of estrogen on skeletal muscle mitochondrial function in ovariectomized rats: a time course study in different fiber types

DP. Role of estrogen on skeletal muscle mitochondrial function in ovariectomized rats: a time course study in different fiber types. J Appl Physiol 116: 779–789, 2014. First published January 23, 2014; doi:10.1152/japplphysiol.00121.2013.—Postmenopausal women are prone to develop obesity and insulin resistance, which might be related to skeletal muscle mitochondrial dysfunction. In a rat model of ovariectomy (OVX), skeletal muscle mitochondrial function was examined at short- and long-term periods after castration. Mitochon-drial parameters in the soleus and white gastrocnemius muscle fibers were analyzed. Three weeks after surgery, there were no differences in coupled mitochondrial respiration (ATP synthesis) with pyruvate, malate, and succinate; proton leak respiration; or mitochondrial reac-tive oxygen species production. However, after 3 wk of OVX, the soleus and white gastrocnemius muscles of the OVX animals showed a lower use of palmitoyl-carnitine and glycerol-phosphate substrates

OsICE1 transcription factor improves photosynthetic performance and reduces grain losses in rice plants subjected to drought

International audienceDrought is a major environmental threat to agriculture sustainability. We have characterised the role of OsICE1, a basic helix-loop-helix (bHLH) transcription factor from rice (Otyza saliva L.), in response to drought. OsICEI gene is constitutively expressed in roots and shoots of rice seedlings grown under control conditions, as well as in response to low temperature, high salinity, and ABA. Nevertheless, in response to drought, OsICE1 is up-regulated in roots. Plants over-expressing OsICE1 (OsICEI-OX) show improved drought tolerance at both vegetative and reproductive stages, whereas OsICE1 silenced plants (OsICE1-RNA1) show decreased drought tolerance in the same phenological stages. Under drought, OsICE1-0X plants show improved net photosynthetic rates and stomatal conductance to water vapour, as well as higher photochemical efficiency of photosystem II and tolerance to photo-inhibition, as compared to the WT and OsICEI-RNAi. In addition, under severe drought, OsICEI-OX plants show lower grain yield losses than WT, while OsICE1-12NAi plants show the highest grain losses. OsICE1-OX and OSICE1-RNAi plants do not differentially respond to ABA, and drought-inducible genes are more responsive in OsICEI-RNAi and less in OsICE1-OX plants (as compared to WT), suggesting that OsICE1 has a central role modulating molecular responses to drought in an ABA-independent way. This role might be mediated by OsWsi18, a LEA encoding gene up regulated in OsICE1-OX rice plants and known to enhance membrane stability under drought