Glycolytic enzyme inhibitors affect pancreatic cancer survival by modulating its signaling and energetics.
OBJECTIVE
The importance of glycolysis in cancer cells is well documented. The effects of inhibiting glycolysis using metabolic inhibitors iodoacetate (IAA), an inhibitor of GAPDHase, and 3-bromopyruvate (3BP), an inhibitor of hexokinase-II, on survival and signaling of pancreatic cancer cells (Panc-1) were investigated.


METHODS
Cellular survival was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Lactate dehydrogenase (LDH) assay was used to analyze the induced necrosis and protein levels were evaluated using Western blot analysis.


RESULTS
The results show that the inhibitors lowered cellular survival and increased cellular necrosis. Mitogenic signaling pathways were affected by 3BP but not by IAA.


CONCLUSIONS
We conclude that there may be a cross-talk between signaling pathways and glycolysis in regulating pancreatic cancer cell survival and signaling. Thus, a combination of agents that inhibit both energy production and cell signaling may provide a novel and effective approach to target pancreatic cancer effectively.
Bhardwaj
Vikas
V
Department of Biomedical and Pharmaceutical Sciences, ISU Biomedical Research Institute, College of Pharmacy, Idaho State University, 921, South 8th Ave., Pocatello, Idaho 83209-8334, USA.
Rizvi
Nisha
N
Lai
Maria B
MB
Lai
James C K
JC
Bhushan
Alok
A
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006593:Hexokinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007461:Iodoacetates / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007461:Iodoacetates; D011773:Pyruvates; C017092:bromopyruvate; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D006593:Hexokinase; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins