Systems Biology Approaches to Cancer Energy Metabolism - Systems Biology of Metabolic and Signaling Networks - page 211

9.3 Glycolysis Fingerprints in Tumor Cells Versus Normal
Cells

Besides the higher glycolytic rate exhibited by tumor cells as compared with
normal ones, the type of isoenzyme expression is another important difference.
HK and PFK-1, which are the main controlling steps of glycolysis in normal cells,
show changes in their regulatory mechanisms in tumor cells. In cancer cells, HK
activity increases 5- to 500-fold (Nakashima et al. 1988 ; Smith 2000 ; Pedersen
et al. 2002 ; Stubbs et al. 2003 ; Mar´n-Hern´ndez et al. 2006 ), and it is preferentially
bound to the outer mitochondrial membrane as compared with the tissue of origin or
with other normal cells. Because of this localization, some authors have suggested
that mitochondrial binding will enable HK to decrease its sensitivity to product
inhibition by G6P (Nakashima et al. 1988 ; Widjojoatmodjo et al. 1990 ), but this
could not be verified experimentally (Mar ´ n-Hern ´ ndez et al. 2006 ).
In normal cells under aerobiosis, PFK-1 has a main role at the onset of the
Pasteur effect through its allosteric inhibition, elicited by some mitochondrial
intermediaries such as ATP, citrate, and H + , which brings about a decrease of the
glycolytic flux. In contrast, PFK-1 activity increases five times in some tumors
versus normal cells (Vora et al. 1985 ; El-Bacha et al. 2003 ) and the expressed
isoform exhibits 5- to 300-fold higher affinity for its allosteric activator F2,6BP
(Oskam et al. 1985 ; Colomer et al. 1987 ; Staal et al. 1987 ), along with one to seven
times lower affinity for ATP and citrate, respectively (Meldolesi et al. 1976 ; Oskam
et al. 1985 ; Staal et al. 1987 ). Furthermore, in cancer cells there is a significant
increase in the F2,6BP concentration due to the higher expression of PFKB-3, a
PFK-2 isoform that maintains an elevated kinase/phosphatase activity ratio leading
to predominating F2,6BP synthesis over its degradation (Yalcin et al. 2009 ). Con-
sequently, elevated levels of F2,6BP as well as AMP and Pi (also PFK-1 allosteric
activators) are found in cancer cells, which circumvents the inhibitory effect of
ATP, citrate, and H + on PFK-1 causing the lack of Pasteur effect in tumor cells
(Eigenbrodt et al. 1985 ; Moreno-S´nchez et al. 2012 ).
Isoenzyme expression changes in tumor cells indicate differences in the struc-
ture of control of glycolysis compared with normal cells. Hence, a Systems Biology
approach appears to be appropriate for addressing the comprehensive genetic and
biochemical remodeling underlying the well-documented increase in glycolysis
shown by cancer cells. Indeed, several kinetic models of glycolysis in erythrocytes
(du Preez et al. 2008 ),

-cells of pancreatic islets (Achs et al. 1991 ), and tumor cells
(Mar ´ n-Hern ´ ndez et al. 2011 ) have been developed. The analysis of this integra-
tive approach as applied to tumor glycolysis is discussed in the next section.

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