production rate and glycolytic fluxes for HeLa cellular cell lines
under conditions of normoxia and hypoxia and for AS-30D cells.
As can be noticed in Fig.7, the entropy production per unit of
time of the glycolysis pathway in HeLa cell line in hypoxic condi-
tions is higher than in normoxia. This indicates, not only how is the
glycolysis process favored under low oxygen conditions, but also
that under these conditions it becomes more robust [106].
It is known that cancerous tumors under conditions of hypoxia
become more resistant and more aggressive [107]. On the other
hand, for the hepatoma AS-30D, the glycolytic flow (29 mmol/
min) is identical to HeLa under conditions of hypoxia, while theS_i
is slightly higher in hepatoma AS-30 (11.028 [J/K min]10^3 )
compared to HeLa in hypoxic conditions (10.1 [J/K min]10^3 ).
The total value of the entropy production rate for HeLa cells is
doubled under Hypoxia conditions (HeLa normoxia¼6866 [J/K
min]10^3 ) as shown in Fig.7.
The increase inS_iunder conditions of hypoxia may be due to
overexpression of transcription regulatory mechanisms favoring the
glycolytic pathway in low oxygen concentration such as HIF-1
(hypoxia-inducible transcription factor). Metabolism of hypoxia
elicits multiple adaptive changes in cellular metabolism, which are
coordinated by HIF-1 and serve to maintain redox homeostasis by
increasing glycolysis and attenuating respiration. Decreased oxida-
tive metabolism is necessary to limit production of reactive oxygen
species (ROS) by the mitochondrial electron transport chain under
hypoxic conditions [108].
HIF-1αstimulates glucose uptake necessary to compensate for
the relative inefficiency of glycolysis, by upregulating glucose mem-
brane transporters, GLUT1 and GLUT3. In addition, HIF-1α
upregulate glycolytic enzymes such as hexokinases and phospho-
glycerate kinase 1 and inhibit mitochondrial respiration by activat-
ing the transcription of pyruvate dehydrogenase kinase (PDK),
which in turn phosphorylates and inactivates pyruvate dehydroge-
nase (PDH).
Also, HIF-1αupregulates lactate dehydrogenase-A to promote
lactate production and regenerate NAD+[109]. HIF-1 maintains
intracellular pH by increasing lactate and proton efflux through
expression of monocarboxylate transporter (MCT)-4, carbonic
anhydrase 9, and Na+–H+exchanger-1 [108].
From the results for the HeLa cell line under conditions of
normoxia and hypoxia and AS-30D cells, the fundamental reactions
in the glycolysis process were identified (Fig.8).
The fundamental postulate follows: those reactions that exhibit
a higher value ofS_i are considered fundamentals in the process
[81]. This statement could be considered an extension of the
“Principle of Maximum Entropy” [110]. The entropy production
rate was normalized in percent using as a baseline the highest value.150 Sheyla Montero et al.