2-Deoxyglucose inhibits chemotherapeutic drug-induced apoptosis in human monocytic leukemia U937 cells with inhibition of c-Jun N-terminal kinase 1/stress-activated protein kinase activation.
Human monocytic leukemia U937 cells undergo apoptosis when treated with antitumor drugs, such as etoposide, camptothecin and mitomycin C. The molecular mechanism of the drug-induced apoptosis is not well understood. In this study, we found that 2-deoxyglucose (2DG), an analog of D-glucose and an inducer of glucose-regulated stress, inhibited anticancer drug-induced but not tumor necrosis factor-alpha-induced apoptosis of U937 cells. 2DG did not reduce initial cellular damage caused by etoposide, an inhibitor of topoisomerase II, suggesting that 2DG affected subsequent cellular responses involved in apoptosis. 2DG inhibited the etoposide-induced activation of c-Jun N-terminal kinase 1/stress-activated protein kinase (JNK1/SAPK) and the subsequent activation of CPP32, both of which are positive regulators for etoposide-induced apoptosis of U937 cells. Our results indicate that 2DG inhibits apoptosis by blocking the signals from cellular DNA damage for JNK1/SAPK activation.
Haga
N
N
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Naito
M
M
Seimiya
H
H
Tomida
A
A
Dong
J
J
Tsuruo
T
T
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis; D002467:Cell Nucleus / Q000187:drug effects; D053938:DNA Fragmentation; D003847:Deoxyglucose / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007951:Leukemia, Myeloid / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha
D000972:Antineoplastic Agents, Phytogenic; D014409:Tumor Necrosis Factor-alpha; D005047:Etoposide; D003847:Deoxyglucose; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases