The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that cancer cells by...The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for thera- peutic interventions in various cancer types.展开更多
G protein-coupled receptors(GPCRs)are the most widely targeted class for approved drugs but only a small portion(-15%)of GPCRs are currently targeted.Work in my laboratory has tested the hypothesis that individual cel...G protein-coupled receptors(GPCRs)are the most widely targeted class for approved drugs but only a small portion(-15%)of GPCRs are currently targeted.Work in my laboratory has tested the hypothesis that individual cell types express previously unrecognized GPCRs that regulate cell function and may be novel drug targets.A key focus has been our efforts to define differential expression(DE)of GPCRs on normal cells versus cells from patients with diseases:pulmonary arterial smooth muscle cells/pulmonary arterial hypertension,lung and cardiac fibroblasts/lung and cardiac fibrosis and pancreatic cells/pancreatic ductal adenocarcinoma(PDAC).To test our hypothesis,we have used unbiased(GPCRomic)approaches(Taqman GPCR arrays and RNA-seq),mining of publicly available datasets(the GTEX database for normal tissues and the Cancer Genome Atlas,TCGA)and studies of signaling and functional activity to validate newly detected GPCRs.The GPCRomic studies reveal that most cell types and tissues express>100 different GPCRs with limited prior data for many highly expressed GPCRs,numerous of which are"orphans"(which lack known physiologic agonists).Numerous GPCRs have DE and alter functionin diseased cells.For example,studies of PDAC tumors/cells and pancreatic cancer-associated fibroblasts(PCAFs)identify two GPCRs with high DE,respectively,in PDAC cells compared to normal pancreatic ductal epithelial cells and in PCAFs compared to normal pancreatic Fs/stellate cells.These two GPCRs:(1)are frequently,highly expressed in PDAC tumors compared to normal pancreas and(2)regulate functional activities that influence the malignant phenotype.Overall,the results indicate the utility of unbiased GPCRomic and data-mining approaches to identify previously unrecognized,functional GPCRs that may contribute to human disease and that may be novel,drug gable targets.展开更多
Mature adipocytes are terminally differentiated somatic cells. Here, we report the successful generation of induced pluripotent stem(i PS) cells from mouse mature adipocytes by forced expression of six transcription f...Mature adipocytes are terminally differentiated somatic cells. Here, we report the successful generation of induced pluripotent stem(i PS) cells from mouse mature adipocytes by forced expression of six transcription factors(Oct4, Sox2, c-Myc, Klf4, Rarc, and Lrh1) with a piggy Bac transposon-based strategy. The resulting i PS cells were pluripotent as evidenced by the fact that they stained positive for alkaline phosphatase, expressed high levels of key pluripotency markers including Oct4, Nanog, and SSEA1,and remained pluripotent on a 2i media. In vitro differentiation of the i PS cells showed that the cell derivatives of all three germ layers could be readily obtained through formation of embryoid bodies. Most importantly, these adipocytederived i PS cells were capable of producing chimera with high frequencies when reintroduced into early-stage embryos and transmitted through the germ line. This study demonstrates that the new six-factor reprogramming technology facilitates the reset of the terminally differentiated adipocytes to the ground state of pluripotency, enabling us to fully explore the potential of mature adipocytes as a viable cell source for regenerative medicine.展开更多
文摘The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for thera- peutic interventions in various cancer types.
基金supported by NIH grants(R21CA202608,R21AG053568)Dept of Defense Grant(W81XWH-14-1-0372)+1 种基金Bristol Myers Squibb,Padres Pedal the Cause PTC2017an ASPET-David Lehr Research Award
文摘G protein-coupled receptors(GPCRs)are the most widely targeted class for approved drugs but only a small portion(-15%)of GPCRs are currently targeted.Work in my laboratory has tested the hypothesis that individual cell types express previously unrecognized GPCRs that regulate cell function and may be novel drug targets.A key focus has been our efforts to define differential expression(DE)of GPCRs on normal cells versus cells from patients with diseases:pulmonary arterial smooth muscle cells/pulmonary arterial hypertension,lung and cardiac fibroblasts/lung and cardiac fibrosis and pancreatic cells/pancreatic ductal adenocarcinoma(PDAC).To test our hypothesis,we have used unbiased(GPCRomic)approaches(Taqman GPCR arrays and RNA-seq),mining of publicly available datasets(the GTEX database for normal tissues and the Cancer Genome Atlas,TCGA)and studies of signaling and functional activity to validate newly detected GPCRs.The GPCRomic studies reveal that most cell types and tissues express>100 different GPCRs with limited prior data for many highly expressed GPCRs,numerous of which are"orphans"(which lack known physiologic agonists).Numerous GPCRs have DE and alter functionin diseased cells.For example,studies of PDAC tumors/cells and pancreatic cancer-associated fibroblasts(PCAFs)identify two GPCRs with high DE,respectively,in PDAC cells compared to normal pancreatic ductal epithelial cells and in PCAFs compared to normal pancreatic Fs/stellate cells.These two GPCRs:(1)are frequently,highly expressed in PDAC tumors compared to normal pancreas and(2)regulate functional activities that influence the malignant phenotype.Overall,the results indicate the utility of unbiased GPCRomic and data-mining approaches to identify previously unrecognized,functional GPCRs that may contribute to human disease and that may be novel,drug gable targets.
基金supported in part by the National Basic Research Program of China(2011CB504004,2010CB945500)the Strategic Program of Stem Cell(XDA01020303)+1 种基金the Knowledge Innovation Program of the Chinese Academy of Sciencesthe National Natural Science Foundation of China(90813033)as well as The Guangdong Key High-end Foreign Experts Program Fund
文摘Mature adipocytes are terminally differentiated somatic cells. Here, we report the successful generation of induced pluripotent stem(i PS) cells from mouse mature adipocytes by forced expression of six transcription factors(Oct4, Sox2, c-Myc, Klf4, Rarc, and Lrh1) with a piggy Bac transposon-based strategy. The resulting i PS cells were pluripotent as evidenced by the fact that they stained positive for alkaline phosphatase, expressed high levels of key pluripotency markers including Oct4, Nanog, and SSEA1,and remained pluripotent on a 2i media. In vitro differentiation of the i PS cells showed that the cell derivatives of all three germ layers could be readily obtained through formation of embryoid bodies. Most importantly, these adipocytederived i PS cells were capable of producing chimera with high frequencies when reintroduced into early-stage embryos and transmitted through the germ line. This study demonstrates that the new six-factor reprogramming technology facilitates the reset of the terminally differentiated adipocytes to the ground state of pluripotency, enabling us to fully explore the potential of mature adipocytes as a viable cell source for regenerative medicine.
