We identified 9 reactions of the 20 that are part of the glycolisis
model (seeFig. 8), for both HeLa and AS-30D cells. Three with
those found by sensitivity analysis (PFK1, GAPDH, ATPase), and
also collected the so-called control points (HK, PFK1, PYR)
[111]. The greater value ofS_iwas found for both cell lines in the
reaction catalyzed by ATPase. This protein, ATPase, consists of a
complex multi-subunit composed by a catalytic domain V1,
responsible for the hydrolysis of ATP and a transmembrane domain
V0 which is a proton channel [112].
The V-ATPase is overexpressed in many types of cancers and is
related to the ability of these invasion and metastases [113]. The
V-ATPase, a cell-specific proton pump, is expressed in the plasma
membranes of human tumor cells and may have a specialized role in
cell growth, differentiation, angiogenesis, and metastasis plays an
important role in the control of intracellular and extracellular pH
[114]. It is involved in the maintenance of a pHintracelular(pHi)
relatively neutral (slightly basic) and pHextracelular (pHe) acid,
which is known as the reverse gradient through pumping H+
from the intracellular medium to vacuoles and the extracellular
medium [115]. In cancerous tissues, the extracellular microenvi-
ronment can produce an increase in the secretion and activation of
proteases and promote the degradation and remodeling of the
extracellular matrix through the activation of proteolytic enzymes,
which contributes to invasion and metastasis [114].
The V-ATPase is involved in the acquisition of a drug-resistant
cellular phenotype and has therefore been identified as a potential
target for cancer treatments [113].Fig. 8Entropy production rate normalized values for fundamental reactions, in HeLa tumor cells in Normoxia
(green) and Hypoxia (orange) conditions and AS-30D (purple) tumor cell. Reaction reported as fundamental by
sensitivity analysis (green arrow), metabolic control analysis (blue arrow) and biochemistry control points (red
arrow)
Parameters Estimation in Phase-Space Landscape Reconstruction of Cell Fate... 151