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Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing
link between aerobic glycolysis and cancer cell proliferation
#MMPMID26543237
De Preter G
; Neveu MA
; Danhier P
; Brisson L
; Payen VL
; Porporato PE
; Jordan BF
; Sonveaux P
; Gallez B
Oncotarget
2016[Jan]; 7
(3
): 2910-20
PMID26543237
show ga
Glucose fermentation through glycolysis even in the presence of oxygen (Warburg
effect) is a common feature of cancer cells increasingly considered as an
enticing target in clinical development. This study aimed to analyze the link
between metabolism, energy stores and proliferation rates in cancer cells. We
found that cell proliferation, evaluated by DNA synthesis quantification, is
correlated to glycolytic efficiency in six cancer cell lines as well as in
isogenic cancer cell lines. To further investigate the link between glycolysis
and proliferation, a pharmacological inhibitor of the pentose phosphate pathway
(PPP) was used. We demonstrated that reduction of PPP activity decreases cancer
cells proliferation, with a profound effect in Warburg-phenotype cancer cells.
The crucial role of the PPP in sustaining cancer cells proliferation was
confirmed using siRNAs against glucose-6-phosphate dehydrogenase, the first and
rate-limiting enzyme of the PPP. In addition, we found that dichloroacetate
(DCA), a new clinically tested compound, induced a switch of glycolytic cancer
cells to a more oxidative phenotype and decreased proliferation. By demonstrating
that DCA decreased the activity of the PPP, we provide a new mechanism by which
DCA controls cancer cells proliferation.
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