Increased sensitivity to glucose starvation correlates with downregulation of glycogen phosphorylase isoform PYGB in tumor cell lines resistant to 2-deoxy-d-glucose

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• 作者：Katherine B. Philips (1)
  Metin Kurtoglu (2)
  Howard J. Leung (1)
  Huaping Liu (2)
  Ningguo Gao (3)
  Mark A. Lehrman (3)
  Timothy G. Murray (4)
  Theodore J. Lampidis (5) (6)
  
• 关键词：2 ; Deoxy ; d ; glucose ; Glucose starvation ; Unfolded protein response ; Glycogen
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2014
• 出版时间：February 2014
• 年：2014
• 卷：73
• 期：2
• 页码：349-361
• 全文大小：1,023 KB
• 作者单位：Katherine B. Philips (1)
  Metin Kurtoglu (2)
  Howard J. Leung (1)
  Huaping Liu (2)
  Ningguo Gao (3)
  Mark A. Lehrman (3)
  Timothy G. Murray (4)
  Theodore J. Lampidis (5) (6)
  
  1. 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
  2. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, PAP Building, Room 115, 1550 NW 10th Ave, Miami, FL, 33136, USA
  3. Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX, 75390-9041, USA
  4. Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, 900 NW 17th St., Miami, FL, 33136, USA
  5. Department of Cell Biology (R-124), University of Miami Miller School of Medicine, 1600 NW 10th Avenue, Rosenstiel Medical Sciences Building #4026/4027, P.O. Box 016960, Miami, FL, 33101, USA
  6. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Avenue, P.O. Box 016960, Miami, FL, 33101, USA
  
• ISSN：1432-0843

文摘

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.