Energy metabolism of leukemia cells: glycolysis versus oxidative phosphorylation.
For generation of energy, cancer cells utilize glycolysis more vigorously than oxidative phosphorylation in mitochondria (Warburg effect). We examined the energy metabolism of four leukemia cell lines by using glycolysis inhibitor, 2-deoxy-d-glucose (2-DG) and inhibitor of oxidative phosphorylation, oligomycin. NB4 was relatively sensitive to 2-DG (IC(50): 5.75 mM), consumed more glucose and produced more lactate (waste product of glycolysis) than the three other cell lines. Consequently, NB4 was considered as a "glycolytic" leukemia cell line. Dependency on glycolysis in NB4 was confirmed by the fact that glucose (+) FCS (-) medium showed more growth and survival than glucose (-) FCS (+) medium. Alternatively, THP-1, most resistant to 2-DG (IC(50): 16.14 mM), was most sensitive to oligomycin. Thus, THP-1 was recognized to be dependent on oxidative phosphorylation. In THP-1, glucose (-) FCS (+) medium showed more growth and survival than glucose (+) FCS (-) medium. The dependency of THP-1 on FCS was explained, at least partly, by fatty acid oxidation because inhibitor of fatty acid β-oxidation, etomoxir, augmented the growth suppression of THP-1 by 2-DG. We also examined the mechanisms by which THP-1 was resistant to, and NB4 was sensitive to 2-DG treatment. In THP-1, AMP kinase (AMPK), which is activated when ATP becomes limiting, was rapidly phosphorylated by 2-DG, and expression of Bcl-2 was augmented, which might result in resistance to 2-DG. On the other hand, AMPK phosphorylation and augmentation of Bcl-2 expression by 2-DG were not observed in NB4, which is 2-DG sensitive. These results will facilitate the future leukemia therapy targeting metabolic pathways.
Suganuma
Kazuto
K
Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
Miwa
Hiroshi
H
Imai
Norikazu
N
Shikami
Masato
M
Gotou
Mayuko
M
Goto
Mineaki
M
Mizuno
Shohei
S
Takahashi
Miyuki
M
Yamamoto
Hidesuke
H
Hiramatsu
Akihito
A
Wakabayashi
Motohiro
M
Watarai
Masaya
M
Hanamura
Ichiro
I
Imamura
Akira
A
Mihara
Hidetsugu
H
Nitta
Masakazu
M
D000963:Antimetabolites / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D009840:Oligomycins / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D014475:Uncoupling Agents / Q000494:pharmacology
D000963:Antimetabolites; D009840:Oligomycins; D014475:Uncoupling Agents; D019344:Lactic Acid; D003847:Deoxyglucose; D005947:Glucose