Systems Biology Approaches to Cancer Energy Metabolism - Systems Biology of Metabolic and Signaling Networks - page 227

the O 2 supply (Sonveaux et al. 2008 ; Mandujano-Tinoco et al. 2013 ); fully blood-
irrigated tumors are then dependent on OxPhos for ATP supply. Thus, the
generalized belief, that mitochondrial function is absent or nonfunctional in cancer
cells, has been challenged by abundant experimental evidence (see for reviews
Moreno-S ´ nchez et al. 2007 ; Ralph et al. 2010a , b ). Consequently, assessment of
OxPhos in cancer cells should not be ignored. In addition, to improve understanding
of the control of ATP supply in cancer cells, our glycolytic model should be
extended to include OxPhos, which will enable us to have a more comprehensive
assessment of the steps that exert the control of energy metabolism. In principle,
this will allow to further substantiate the proposal of a multi-target versus mono-
target therapy of the most flux- and metabolite concentration-controlling reactions.
So far modeling OxPhos in cancer cells has not been reported. However,
advances have been carried out in modeling the Krebs cycle (KC) and OxPhos in
normal cells. Kohn et al. ( 1979 ) built a kinetic model of the KC to explain the
sequence of biochemical events that control metabolism of exogenous pyruvate in
perfused rat hearts. This model made an important contribution in providing a
useful repository data of kinetic mechanisms for the KC reactions (Wu et al. 2007 ).
Another kinetic model of KC in rat liver mitochondrial was used to study the effect
of salicylate on the energy metabolism and establish the mechanisms of the
hepatotoxicity of this compound (Mogilevskaya et al. 2006 ).
Regarding OxPhos, several mathematical models have been published which
predict the flux-control distribution and the ATP/ADP ratios, electrochemical H +
gradient, and rates of O 2 consumption and ATP synthesis in isolated mitochondria
under different metabolic states (reviewed by Mazat et al. 2010 ). The next step has
been the integral modeling of both KC and OxPhos. With the use of simplified rate
equations for OxPhos reactions, a mathematical model of cardiac mitochondria
metabolism has been developed to predict how ATP supply may be governed by
fluctuations in the matrix concentration of Ca 2+ , a strong allosteric modulator of KC
dehydrogenases (Cortassa et al. 2003 ), and the dynamics of other relevant ions such
as Na + , Pi, and H + (Wu et al. 2007 ; Wei et al. 2011 ). Although these models have
been able to reproduce qualitatively and semiquantitatively the in vivo pathway
behavior, several kinetic parameters/variables were adjusted or obtained under
non-physiological experimental conditions, yielding some unrealistic responses
and limiting their use for understanding the controlling/regulatory mechanisms of
the pathway.
The kinetic database of KC and OxPhos in tumor cells is still incomplete
hindering model development. Like in glycolysis, some cancer cells show increased
activity of several KC/OxPhos enzymes (Dietzen and Davis 1993 ) and expression
of specific isoforms with different kinetic values and regulatory properties to those
of the isoforms expressed in normal cells/mitochondria (Siess et al. 1976 ). These
changes dissuade the use of the kinetic parameters/variables reported for enzymes/
transporters of normal cells in the modeling of cancer energy metabolism. Then, the
immediate task at hand is to determine the kinetic parameters of each Krebs cycle
and OxPhos enzyme/transporter in isolated mitochondria from cancer cells to build
the corresponding kinetic model.