Isoenzymes of hexokinase, 6-phosphogluconate dehydrogenase, phosphoglucomutase and lactate dehydrogenase in uterine cancer. Marshall M J,Neal F E,Goldberg D M British journal of cancer Electrophoresis of cytosol prepared from normal and malignant tissue samples of uterine cervix and endometrium revealed interesting differences which may be relevant to the characteristic alterations in glucose metabolism associated with tumour development. Hexokinase II was detected in 30% of the cancer material from both sources, but in none of the samples of normal cervix. A duplet band of 6-phosphogluconate dehydrognease was seen in the majority of the cancer samples but in no sample of normal cervix; it appeared to be partly due to ageing of the sample, and is not phenotypically related to the malignant process. Analysis of genetic variance for phosphoglucomutase at the PGM1 locus revealed a highly significant excess of the PGM1-1 phenotype in patients with cancer of the endometrium, which may reflect susceptibility to endometrial cancer in patients with this phenotype. At the PGM2 locus, samples of malignant cervix were deficient in "Band f" compared with normal cervix samples, all of which showed this band. Conversely, gene products of the PGM3 locus were found in most samples of malignant cervix and a small minority of normal cervix samples. Compared with the isomorphic distribution of lactate dehydrogenase enzymes in normal uterine tissue, cancers showed a shift towards either a more anodal or a more cathodal pattern. The former may be associated with tumours enjoying a good oxygen supply, and the latter with tumours which, because of their depth or poor blood supply have to function under less aerobic conditions. 10.1038/bjc.1979.192
    Distinction of seventy-one cultured human tumor cell lines by polymorphic enzyme analysis. Wright W C,Daniels W P,Fogh J Journal of the National Cancer Institute A large collection of cultured human tumor cell lines was characterized for the phenotypes of 16 polymorphic enzyme loci: ACP1, ADA, AK1, ESD, FUCA, GLO1, GOT2, G6PD, ME2, PEPA, PEPB, PEPC, PEPD, PGD, PGM1, and PGM3 primarily to detect and monitor against cell line contamination. Among 100 highly characterized cell lines, 59 lines from different patients and 6 pairs of lines (each pair from the same patient's tumor) had unique phenotype combinations and were therefore presumed to be authentic, uncontaminated cell lines. Besides these 71 lines, the remaining 29 lines consisted of several small groups of two to three lines, each group having a different combination and being among the more frequent in the normal population. The 29 lines, therefore, were not suspected to be contaminants. Among unusual findings were the ME2 1 plus 2 phenotype determined for two bladder tumor lines, a G6PD A phenotype found in a line of Caucasian origin determined not to be a HeLa contaminant, and asymmetrical heterozygous phenotypes in several lines. Except for kidney tumor lines, there was no correlation of adenosine deaminase tissue isoenzymes between tumor lines and normal tissues of origin. For several enzymes significant deviations were found in proportions of the phenotypes observed in Caucasian cell lines from expected proportions on the basis of normal population data, indicating possible natural selection among these lines in tissue culture or among the patients of origin.
    Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis. Curtis Marion,Kenny Hilary A,Ashcroft Bradley,Mukherjee Abir,Johnson Alyssa,Zhang Yilin,Helou Ynes,Batlle Raquel,Liu Xiaojing,Gutierrez Nuria,Gao Xia,Yamada S Diane,Lastra Ricardo,Montag Anthony,Ahsan Nagib,Locasale Jason W,Salomon Arthur R,Nebreda Angel R,Lengyel Ernst Cell metabolism Successful metastasis requires the co-evolution of stromal and cancer cells. We used stable isotope labeling of amino acids in cell culture coupled with quantitative, label-free phosphoproteomics to study the bidirectional signaling in ovarian cancer cells and human-derived, cancer-associated fibroblasts (CAFs) after co-culture. In cancer cells, the interaction with CAFs supported glycogenolysis under normoxic conditions and induced phosphorylation and activation of phosphoglucomutase 1, an enzyme involved in glycogen metabolism. Glycogen was funneled into glycolysis, leading to increased proliferation, invasion, and metastasis of cancer cells co-cultured with human CAFs. Glycogen mobilization in cancer cells was dependent on p38α MAPK activation in CAFs. In vivo, deletion of p38α in CAFs and glycogen phosphorylase inhibition in cancer cells reduced metastasis, suggesting that glycogen is an energy source used by cancer cells to facilitate metastatic tumor growth. 10.1016/j.cmet.2018.08.007
    Central nervous involvement is common in PGM1-CDG. Radenkovic Silvia,Witters Peter,Morava Eva Molecular genetics and metabolism PGM1, the enzyme responsible for the reversible inter-conversion of glucose-1-P and glucose-6-P, is also involved in glycosylation, leading to a wide range of clinical manifestations, such as congenital malformations, hypoglycemia, hormonal dysregulation, myopathy, hepatopathy, and cardiomyopathy. So far, PGM1 deficiency has not been associated with central nervous system involvement or intellectual disability. Seizures and neurologic involvement in PGM1-CDG were thought to be a consequence of hypoglycemia. We reviewed all reported PGM1 deficient patients for the presence of the central nervous system involvement, their treatment and disease history. We detected 17 patients out of the 41 reported PGM1-CDG cases with significant neurologic involvement. Several of these patients had no severe hypoglycemic episodes, or were adequately treated for hypoglycemia with no recurrent episodes of low blood sugars, while one patient had no reported hypoglycemic episodes. We suggest that neurological symptoms are frequent in PGM1-CDG and could present even in the absence of hypoglycemia. The central nervous system should be assessed early on during the diagnostic process to optimize outcome in patients with PGM1-CDG. 10.1016/j.ymgme.2018.08.008
    The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG. Radenkovic Silvia,Bird Matthew J,Emmerzaal Tim L,Wong Sunnie Y,Felgueira Catarina,Stiers Kyle M,Sabbagh Leila,Himmelreich Nastassja,Poschet Gernot,Windmolders Petra,Verheijen Jan,Witters Peter,Altassan Ruqaiah,Honzik Tomas,Eminoglu Tuba F,James Phillip M,Edmondson Andrew C,Hertecant Jozef,Kozicz Tamas,Thiel Christian,Vermeersch Pieter,Cassiman David,Beamer Lesa,Morava Eva,Ghesquière Bart American journal of human genetics Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG. 10.1016/j.ajhg.2019.03.003
    The association between alcohol metabolism and genetic variants of ADH1A, SRPRB, and PGM1 in Korea. Lee Yoo Jeong,Yoo Min-Gyu,Kim Hyeon-Kyeong,Jang Han Byul,Park Keon Jae,Lee Hye-Ja,Kim Sung-Gon,Park Sang Ick Alcohol (Fayetteville, N.Y.) BACKGROUND:Excessive alcohol consumption is a major public health problem in East Asian countries. Alcohol use leads to a cascade of problems including increased chances of risky behavior and a wide range of negative health consequences, from alcoholic liver disease to upper gastric and liver cancer. These alcohol effects are known to be influenced by ethnic variability and genetics. METHODS:In this study, subjects were administered a single dose of alcohol (0.6 g/kg for men or 0.4 g/kg for women), and blood alcohol and acetaldehyde concentrations were measured eight times over 5 hours. To investigate genetically susceptible factors to alcohol metabolism, we selected single-nucleotide polymorphisms (SNP) of genes identified by prior genetic association studies for alcohol metabolism, alcohol consumption, alcohol dependence, and related traits, and performed genotyping on all subjects (n = 104). RESULTS:We identified variations in the ADH1A, SRPRB, and PGM1 genes, which are directly associated with blood alcohol or acetaldehyde concentrations. Namely, the T allele of SRPRB rs17376019 and the C allele of PGM1 rs4643 were associated with lower blood alcohol levels, while the ADH1 rs1229976 C allele group exhibited markedly higher blood acetaldehyde levels than those of the ADH1 rs1229976 T allele group. CONCLUSION:This study demonstrates that genetic variations in ADH1A, SRPRB, and PGM1 are associated with variations in blood alcohol and acetaldehyde concentration after alcohol intake. 10.1016/j.alcohol.2019.03.004
    Effective electrochemotherapy with curcumin in MDA-MB-231-human, triple negative breast cancer cells: A global proteomics study. Mittal Lakshya,Aryal Uma K,Camarillo Ignacio G,Raman Vishak,Sundararajan Raji Bioelectrochemistry (Amsterdam, Netherlands) Curcumin (Cur), the yellow pigment of well-known turmeric (Curcuma longa L.) is effective in multiple cancers including triple negative breast cancer (TNBC). In combination with electrical pulses (EP), enhanced effects of curcumin (Cur + EP) are observed in TNBC cells. To gain insights into the mechanisms of enhanced anticancer effects of Cur + EP, we studied the proteins involved in the anticancer activity of Cur + EP in MDA-MB-231, human TNBC cells using high-throughput global proteomics. A curcumin dose of 50 μM was applied with eight, 1200 V/cm, 100 μs pulses, the most commonly used electrochemotherapy (ECT) parameter in clinics. Results show that the Cur + EP treatment reduced the clonogenic ability in MDA-MB-231 cells, with the induction of apoptosis. Proteomic analysis identified a total of 1456 proteins, of which 453 proteins were differentially regulated, including kinases, heat shock proteins, transcription factors, structural proteins, and metabolic enzymes. Eight key glycolysis proteins (ALDOA, ENO2, LDHA, LDHB, PFKP, PGM1, PGAM1 and PGK1) were downregulated in Cur + EP from Cur. There was a switch in the metabolism with upregulation of 10 oxidative phosphorylation pathway proteins and 8 tricarboxylic acid (TCA) cycle proteins in the Cur + EP sample, compared to curcumin. These results provide novel systematic insights into the mechanisms of ECT with curcumin. 10.1016/j.bioelechem.2019.107350
    Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking. Jin Guang-Zhi,Zhang Yajuan,Cong Wen-Ming,Wu Xueyuan,Wang Xiongjun,Wu Siyang,Wang Siyao,Zhou Weiping,Yuan Shengxian,Gao Hong,Yu Guanzhen,Yang Weiwei PLoS biology Glycogen metabolism commonly altered in cancer is just beginning to be understood. Phosphoglucomutase 1 (PGM1), the first enzyme in glycogenesis that catalyzes the reversible conversion between glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P), participates in both the breakdown and synthesis of glycogen. Here, we show that PGM1 is down-regulated in hepatocellular carcinoma (HCC), which is associated with the malignancy and poor prognosis of HCC. Decreased PGM1 expression obstructed glycogenesis pathway, which leads to the increased flow of glucose into glycolysis, thereby promoting tumor cell proliferation and HCC development. The loss of forkhead box protein J2 (FOXJ2), at least partly due to low genomic copy number in HCC, releases cellular nucleic acid-binding protein (CNBP), a nucleic acid chaperon, to bind to and promote G-quadruplex formation in PGM1 promoter and therefore decreases PGM1 expression. In addition, integrated analyses of PGM1 and FOXJ2 expression provide a better prediction for the malignance and prognosis of HCC. This study establishes a tumor-suppressive role of PGM1 by regulating glucose trafficking and uncovers a novel regulatory mechanism of PGM1 expression. 10.1371/journal.pbio.2006483