TY - JOUR
T1 - Induction of erythroid differentiation is associated with inhibition of glycolysis and a decrease in fructose 2,6-bisphosphate levels
AU - Scher, Barbara M.
AU - Chen, Jonathan Y.H.
AU - Fuksina, Inna
AU - Waxman, Samuel
AU - Scher, William
PY - 1997
Y1 - 1997
N2 - The fraction of glucose metabolized to lactate is dramatically reduced during erythroid differentiation of mouse erythroleukemia (MEL) cells induced by dimethyl sulfoxide (DMSO), hexamethylene bisacetamide (HMBA), or sodium butyrate treatment. In order to determine the mechanism of the reduction in lactate production, several enzymatic steps in glucose catabolism were investigated. No changes in glycolytic enzyme levels were found during differentiation that could account for the alteration in lactate production and alterations in pyruvate kinase activity are known not to occur during MEL cell differentiation. Further, utilizing D-mannoheptulose, a specific inhibitor of hepatic- /tumor-specific glucokinase, no dependence on the activity of this enzyme for growth or differentiation was observed. Therefore, the possibility was entertained that the decrease in lactate production reflected a decrease in fructose 2,6-bisphosphate (F-2,6-P2) which is a major regulator of the lactate production due to its ability to allosterically stimulate phosphofructokinase-1 (PFK-1) activity. PFK-1 cannot function in the absence of F-2,6-P2 when only a suboptimal concentration of one of its substrates, fructose-6-phosphate (F-6-P), is present. When assayed under limiting F-6-P concentrations, it was found that following DMSO- or HMBA-induced differentiation, PFK-1 activity was decreased 7-20-fold. This finding suggested that F-2,6-P2 levels might be controlling lactate production in this system. In keeping with this idea, marked decreases in F- 2,6-P2 levels were found to occur during DMSO- or HMBA-induced differentiation. These data suggest that decreasing F-2,6-P2 levels account for the decrease in lactate accumulation that occurs during MEL cell differentiation.
AB - The fraction of glucose metabolized to lactate is dramatically reduced during erythroid differentiation of mouse erythroleukemia (MEL) cells induced by dimethyl sulfoxide (DMSO), hexamethylene bisacetamide (HMBA), or sodium butyrate treatment. In order to determine the mechanism of the reduction in lactate production, several enzymatic steps in glucose catabolism were investigated. No changes in glycolytic enzyme levels were found during differentiation that could account for the alteration in lactate production and alterations in pyruvate kinase activity are known not to occur during MEL cell differentiation. Further, utilizing D-mannoheptulose, a specific inhibitor of hepatic- /tumor-specific glucokinase, no dependence on the activity of this enzyme for growth or differentiation was observed. Therefore, the possibility was entertained that the decrease in lactate production reflected a decrease in fructose 2,6-bisphosphate (F-2,6-P2) which is a major regulator of the lactate production due to its ability to allosterically stimulate phosphofructokinase-1 (PFK-1) activity. PFK-1 cannot function in the absence of F-2,6-P2 when only a suboptimal concentration of one of its substrates, fructose-6-phosphate (F-6-P), is present. When assayed under limiting F-6-P concentrations, it was found that following DMSO- or HMBA-induced differentiation, PFK-1 activity was decreased 7-20-fold. This finding suggested that F-2,6-P2 levels might be controlling lactate production in this system. In keeping with this idea, marked decreases in F- 2,6-P2 levels were found to occur during DMSO- or HMBA-induced differentiation. These data suggest that decreasing F-2,6-P2 levels account for the decrease in lactate accumulation that occurs during MEL cell differentiation.
KW - Dimethyl sulfoxide
KW - Erythroid differentiation
KW - Erythroleukemia
KW - Fructose 2,6- bisphosphate
KW - Glucose metabolism
KW - Hexamethylene bisacetamide
KW - Lactate
KW - Phosphofructokinase
UR - http://www.scopus.com/inward/record.url?scp=0030809619&partnerID=8YFLogxK
U2 - 10.3892/ijo.11.5.1135
DO - 10.3892/ijo.11.5.1135
M3 - Article
AN - SCOPUS:0030809619
SN - 1019-6439
VL - 11
SP - 1135
EP - 1140
JO - International Journal of Oncology
JF - International Journal of Oncology
IS - 5
ER -