Glucose-dependent active ATP depletion by koningic acid kills high-glycolytic cells.
Many types of cancer cells depend heavily on glycolysis for energy production even in aerobic conditions. We found that koningic acid (KA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), selectively kills high-glycolytic cells through glucose-dependent active ATP deprivation. Out of seven tumor cell lines tested, growth of six cell lines, which had high glycolytic capacity, was inhibited by KA, whereas three normal cell lines, which had low glycolytic activity, were insensitive to KA. The growth inhibition and caspase-independent cell death in sensitive cells were related to severe ATP depletion that was promoted by glucose phosphorylation. Although GAPDH was completely inhibited in KA-insensitive CHO-K1 cells, KA-mediated ATP depletion was less extensive and transient, possibly due to utilization of ketogenic essential amino acids as energy source. KA suppressed Ehrlich ascites tumor growth in vivo and benefited the survival of the affected mice.
Kumagai
Shohei
S
Department of Applied Biological Science, Tokyo Noko University, 3-5-8 Saiwaicho, Fuchu-shi, Tokyo 183-8509, Japan.
Narasaki
Ritsuko
R
Hasumi
Keiji
K
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000473:pathology / Q000503:physiopathology*; D012717:Sesquiterpenes / Q000008:administration & dosage
D012717:Sesquiterpenes; C027285:heptelidic acid; D000255:Adenosine Triphosphate; D005947:Glucose