title: Increased sensitivity to glucose starvation correlates with downregulation of glycogen phosphorylase isoform PYGB in tumor cell lines resistant to 2-deoxy-D-glucose.
abstract: BACKGROUND
  As tumors evolve, they upregulate glucose metabolism while also encountering intermittent periods of glucose deprivation. Here, we investigate mechanisms by which pancreatic cancer cells respond to therapeutic (2-deoxy-D-glucose, 2-DG) and physiologic (glucose starvation, GS) forms of glucose restriction.
  
  
  METHODS
  From a tumor cell line (1420) that is unusually sensitive to 2-DG under normoxia, low (14DG2)- and high (14DG5)-dose resistant cell lines were selected and used to probe the metabolic pathways involved with their response to different forms of glucose deprivation.
  
  
  RESULTS
  Muted induction of the unfolded protein response was found to correlate with resistance to 2-DG. Additionally, 14DG2 displayed reduced 2-DG uptake, while 14DG5 was cross-resistant to tunicamycin, suggesting it has enhanced ability to manage glycosylation defects. Conversely, 2-DG-resistant cell lines were more sensitive than their parental cell line to GS, which coincided with lowered levels of glycogen phosphorylase (PYGB) and reduced breakdown of glycogen to glucose in the 2-DG-resistant cell lines. Moreover, by inhibiting PYGB in the parental cell line, sensitivity to GS was increased.
  
  
  CONCLUSIONS
  Overall, the data demonstrate that the manner in which glucose is restricted in tumor cells, i.e., therapeutic or physiologic, leads to differential biological responses involving distinct glucose metabolic pathways. Moreover, in evolving tumors where glucose restriction occurs, the identification of PYGB as a metabolic target may have clinical application.
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, 1550 NW 10th Avenue, Fox Building #406, Miami, FL, 33136, USA, KPhilips@med.miami.edu.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Philips
authors.forename: Metin
authors.initials: M
authors.lastname: Kurtoglu
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Leung
authors.forename: Huaping
authors.initials: H
authors.lastname: Liu
authors.forename: Ningguo
authors.initials: N
authors.lastname: Gao
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lehrman
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Murray
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Lampidis
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D015536:Down-Regulation; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism*; D024981:Glycogen Phosphorylase / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007527:Isoenzymes; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D014408:Biomarkers, Tumor; D007527:Isoenzymes; D003847:Deoxyglucose; D024981:Glycogen Phosphorylase; D005947:Glucose