and oncogenic drivers and is transcriptionally upregulated by
MYC [122].
The HKII isoform was reported by Mathupala et al. [123] like
“cancer’s double-edged sword.” On the one hand, it facilitates and
safeguards the malignancy of the tumors when it is attached to the
mitochondria [123, 122]. On the other hand, the activity of the
mitochondrial HKII shows that it is required by growth-inducing
factors of cell survival, and by protein kinase B (AKT) [123]. In
addition the binding of the HKII to the mitochondrial membrane
directs the inhibition of apoptosis, the mechanism by which this
occurs is still unknown. HK is not only important for maintaining
high glycolysis rates but is crucial for tumor survival [120].
In normal differentiated adult cells, intracellular pH is generally
~7.2 and lower than the extracellular pH of ~7.4. Deregulated pH
is emerging as a hallmark of cancer [16] because cancers show a
“reversed” pH gradient with a constitutively increased intracellular
pHithat is higher than the extracellular pHe. The increase in pHiin
cancer cells seems paradoxical considering the high proliferation of
these and the high glycolytic flows that generate acid metabolites.
However, changes in the expression or activity of pumps and trans-
porters in the plasma membrane facilitate efflux of H+and maintain
a high pHiand a low pHe[124].
The rate of entropy production for AS30D and HeLa tumor
cells under conditions of normoxia and hypoxia was evaluated for a
range of pH values from 6.2 to 7.4. Figure9 shows a marked
correlation between the rate of entropy production of reaction
14 (ATPase), previously reported as the one exhibiting the highest
S_iand pHe.
As can be seen (Fig.9), when intracellular pHigets lower, also
does the entropy production rate, which measures the loss of the
process robustness with lower intracellular pHi.
Cytoplasmic pH has been shown to play a crucial role in multi-
ple cell functions including the control of cell growth and prolifer-
ation and programmed cell death. Intracellular acidification has
been reported to be a sign of apoptosis in a variety of cancer cells
[125]. Some recent reports have shown that the intracellular pH
plays a key role in determining the way cancer cells obtain energy.
Thus, an alkaline pHidrives aerobic glycolysis and an acidic pHi
drives oxidative phosphorylation [125].
The pHicould rapidly decrease and this would be lethal for the
cancer cell if it were not compensated for by the increase in the
export of protons, resulting in an acidification of the extracellular
medium causing the inverse gradient of pH.
A characteristic feature of cancer cells and especially highly
aggressive cells is overexpression and increased activity of multiple
transporters and regulatory enzymes of pH such as carbonic anhy-
drase which acidify the extracellular space by importingParameters Estimation in Phase-Space Landscape Reconstruction of Cell Fate... 153