Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis

Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.     

具有三个CM公共值的亚纯函数的唯一性

本文指出仪洪勋和Brosch G在具有三个判别的CM公共值的亚纯函数的唯一性定理中,关于对数函数的导数是整函数的推导,可以用指数函数求导的方法来证明.改进了仪洪勋和Brosch G关于重值与唯一性定理.     

Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia

Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.     

Pain relief by xenograft of subarachnoid microencapsulated bovine chromaffin cells in cancer patients

The bovine chromaffin cells (BCC) implanted into the subarachnoid space can release analgesic substances such as opioid peptides and ealeeholamines. Clinical trials have provided the evidence that the implantation of polyvinylchloride ( PVC) hollow fiber encapsulated BCC by surgery can relief the pain in cancer patients. In the present study, BCC were encapsulated in alginate-polylysine-alginate (APA) mieroencapsules which protect the grafting of xenogeneic cells from host immune system anil allow BCC to function effectively without using immunosuppression agents. The microencapsulated BCCs (5 X 106~—8 X 106) were transplanted into the subarachnoid space I^._s of 17 patients who suffered from chronic cancer pain and had to have long-term administration of analgesics. The pain scores and morphine intake tesl showed that microencapsulated BCC graft totally stopped the chronic pain in three of the patients over a period of 200 days and in the other three over a period of 100 days. The resulls suggesl thai APA microencapsulated BCC xenotransplantation could be a novel alternative approach to managing pain of cancer patients.