Ca2+-induced changes in energy metabolism and viability of melanoma cells.
Cancer cells are characterized by a high rate of glycolysis, which is their primary energy source. We show here that a rise in intracellular-free calcium ion (Ca2+), induced by Ca2+-ionophore A23187, exerted a deleterious effect on glycolysis and viability of B16 melanoma cells. Ca2+-ionophore caused a dose-dependent detachment of phosphofructokinase (EC 2.7.1.11), one of the key enzymes of glycolysis, from cytoskeleton. It also induced a decrease in the levels of glucose 1,6-bisphosphate and fructose 1,6-bisphosphate, the two stimulatory signal molecules of glycolysis. All these changes occurred at lower concentrations of the drug than those required to induce a reduction in viability of melanoma cells. We also found that low concentrations of Ca2+-ionophore induced an increase in adenosine 5'-triphosphate (ATP), which most probably resulted from the increase in mitochondrial-bound hexokinase, which reflects a defence mechanism. This mechanism can no longer operate at high concentrations of the Ca2+-ionophore, which causes a decrease in mitochondrial and cytosolic hexokinase, leading to a drastic fall in ATP and melanoma cell death. The present results suggest that drugs which are capable of inducing accumulation of intracellular-free Ca2+ in melanoma cells would cause a reduction in energy-producing systems, leading to melanoma cell death.
Glass-Marmor
L
L
Health Sciences Research Center, Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Penso
J
J
Beitner
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D002470:Cell Survival; D004734:Energy Metabolism / Q000502:physiology*; D005635:Fructosediphosphates / Q000378:metabolism; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D010732:Phosphofructokinase-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D005635:Fructosediphosphates; D007476:Ionophores; D000001:Calcimycin; D000255:Adenosine Triphosphate; D006593:Hexokinase; D010732:Phosphofructokinase-1; C029063:fructose-1,6-diphosphate; D002118:Calcium