246
T. Amemiya et al.
15.1 Introduction
Glycolytic oscillations are spatiotemporal oscillations in the concentrations of
metabolic intermediates in cells, and this phenomenon has been the focus of theoretical and experimental studies in rhythmic behaviours at the cellular level [21]. They
have been reported in several cell types such as yeast cells [3, 16, 24, 44, 54, 60],
pancreatic β-cells [7, 8], ventricular myocytes [66], and cancer cells [4, 5, 19, 30].
The mechanism of intracellular glycolytic oscillations and their synchronisation have
been studied intensively using yeast, Saccharomyces cerevisiae, for almost 60 years
[13].
In 1967, glycolytic oscillations in cancer cells were reported for the first time
[30]. Oscillations of metabolic intermediates, such as nicotinamide adenine dinucleotide (NAD
+ ), fructose 1,6-bisphosphate, and adenosine triphosphate (ATP), were
observed in aerobic suspensions of intact Ehrlich ascites tumour cells obtained from
Swiss white mice. However, so far, no studies have reported an evidence of glycolytic
oscillations in cancer cells in individual cell level, and we have previously reported
the oscillations in HeLa cervical cancer cells [5].
This chapter reviews the first direct observation of glycolytic oscillations in HeLa
cervical and DU145 prostate cancer cells, and presents a mathematical model to
explain the mechanism of their oscillations and reproduce the experimental results.
Biomedical implications obtained from the analyses of the oscillatory dynamics are
also presented: the more the malignancy of cancer cells, the more they tend to exhibit
glycolytic oscillations with higher frequencies.
15.2 Mechanism of Glycolytic Oscillations in Cancer Cells
The mechanism of the glycolytic oscillations in cancer cells can be compared with
glycolytic control reactions in yeast as shown in Fig. 15.1. The core oscillatory
mechanism is the adenosine diphosphate (ADP) dependent activation of glycolytic
products via allosteric enzyme phosphofructokinase (PFK), and its subsequent inhibition by ATP. Although it is now recognized that interactions with mitochondria
are extensive [34] even at low physiological and pathophysiological levels of tissue
and cytosolic oxygen [36]. Our understanding of this basic oscillatory mechanism
will be improved by considering interactions between cytosolic glycolytic pathway
and mitochondrial oxidative phosphorylation such as reduced nicotinamide adenine
dinucleotide (NADH) transport via malate-aspartate shuttle [23, 33].
It is also noted that during the period NADH fluorescence is being measured,
cancer cells are not in a replicative state. The glycolytic dynamics would vary significantly in cells in replicative and non-replicative states, and so the applicability of the
present studies to the non-replicative state will be limited. Nonetheless, the dynamics
of glycolytic oscillations reflects glycolytic activities in cancer cells, and therefore
can be applied to a biomedical diagnosis of cancer, as discussed later.
T. Amemiya et al.
15.1 Introduction
Glycolytic oscillations are spatiotemporal oscillations in the concentrations of
metabolic intermediates in cells, and this phenomenon has been the focus of theoretical and experimental studies in rhythmic behaviours at the cellular level [21]. They
have been reported in several cell types such as yeast cells [3, 16, 24, 44, 54, 60],
pancreatic β-cells [7, 8], ventricular myocytes [66], and cancer cells [4, 5, 19, 30].
The mechanism of intracellular glycolytic oscillations and their synchronisation have
been studied intensively using yeast, Saccharomyces cerevisiae, for almost 60 years
[13].
In 1967, glycolytic oscillations in cancer cells were reported for the first time
[30]. Oscillations of metabolic intermediates, such as nicotinamide adenine dinucleotide (NAD
+ ), fructose 1,6-bisphosphate, and adenosine triphosphate (ATP), were
observed in aerobic suspensions of intact Ehrlich ascites tumour cells obtained from
Swiss white mice. However, so far, no studies have reported an evidence of glycolytic
oscillations in cancer cells in individual cell level, and we have previously reported
the oscillations in HeLa cervical cancer cells [5].
This chapter reviews the first direct observation of glycolytic oscillations in HeLa
cervical and DU145 prostate cancer cells, and presents a mathematical model to
explain the mechanism of their oscillations and reproduce the experimental results.
Biomedical implications obtained from the analyses of the oscillatory dynamics are
also presented: the more the malignancy of cancer cells, the more they tend to exhibit
glycolytic oscillations with higher frequencies.
15.2 Mechanism of Glycolytic Oscillations in Cancer Cells
The mechanism of the glycolytic oscillations in cancer cells can be compared with
glycolytic control reactions in yeast as shown in Fig. 15.1. The core oscillatory
mechanism is the adenosine diphosphate (ADP) dependent activation of glycolytic
products via allosteric enzyme phosphofructokinase (PFK), and its subsequent inhibition by ATP. Although it is now recognized that interactions with mitochondria
are extensive [34] even at low physiological and pathophysiological levels of tissue
and cytosolic oxygen [36]. Our understanding of this basic oscillatory mechanism
will be improved by considering interactions between cytosolic glycolytic pathway
and mitochondrial oxidative phosphorylation such as reduced nicotinamide adenine
dinucleotide (NADH) transport via malate-aspartate shuttle [23, 33].
It is also noted that during the period NADH fluorescence is being measured,
cancer cells are not in a replicative state. The glycolytic dynamics would vary significantly in cells in replicative and non-replicative states, and so the applicability of the
present studies to the non-replicative state will be limited. Nonetheless, the dynamics
of glycolytic oscillations reflects glycolytic activities in cancer cells, and therefore
can be applied to a biomedical diagnosis of cancer, as discussed later.