Acid gradient across plasma membrane can drive phosphate bond synthesis in cancer
cells: acidic tumor milieu as a potential energy source
#MMPMID25874623
Dhar G
; Sen S
; Chaudhuri G
PLoS One
2015[]; 10
(4
): e0124070
PMID25874623
show ga
Aggressive cancers exhibit an efficient conversion of high amounts of glucose to
lactate accompanied by acid secretion, a phenomenon popularly known as the
Warburg effect. The acidic microenvironment and the alkaline cytosol create a
proton-gradient (acid gradient) across the plasma membrane that represents
proton-motive energy. Increasing experimental data from physiological relevant
models suggest that acid gradient stimulates tumor proliferation, and can also
support its energy needs. However, direct biochemical evidence linking
extracellular acid gradient to generation of intracellular ATP are missing. In
this work, we demonstrate that cancer cells can synthesize significant amounts of
phosphate-bonds from phosphate in response to acid gradient across plasma
membrane. The noted phenomenon exists in absence of glycolysis and mitochondrial
ATP synthesis, and is unique to cancer. Biochemical assays using viable cancer
cells, and purified plasma membrane vesicles utilizing radioactive phosphate,
confirmed phosphate-bond synthesis from free phosphate (Pi), and also
localization of this activity to the plasma membrane. In addition to ATP,
predominant formation of pyrophosphate (PPi) from Pi was also observed when
plasma membrane vesicles from cancer cells were subjected to trans-membrane acid
gradient. Cancer cytosols were found capable of converting PPi to ATP, and also
stimulate ATP synthesis from Pi from the vesicles. Acid gradient created through
glucose metabolism by cancer cells, as observed in tumors, also proved critical
for phosphate-bond synthesis. In brief, these observations reveal a role of
acidic tumor milieu as a potential energy source and may offer a novel
therapeutic target.
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