2. fact, two inverse streams of chemical reactions occur

2. Cancer Metabolism

 

2.1. The cancer metabolic pathways
are reprogrammed

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What greatly distinguishes non-living and
living matter is the capability to perform biochemical reactions in the
interest of self-maintenance. Metabolism is the set of reactions needed to
convert nutrients into energy to run cellular processes and synthesize the
molecular “building blocks” of the cell, derived from nutrients such as amino
acids, lipids and carbohydrates. In fact, two inverse streams of chemical
reactions occur in the cells: (1) the catabolic pathways that break down
organic matters into smaller molecules and energy, and (2) the anabolic
pathways that builds up the molecules necessary to the cell, such as proteins
and nucleic acids, using the small molecules and the energy from the
catabolism.

Most, if not all, cancer cells undergo a
complex metabolic reprogramming to satisfy the increased demands of
macromolecules and energy for unrestrained proliferation (Sciacovelli, Gaude,
Hilvo, & Frezza, 2014) and begin anabolic energy pathways to deal with
hypoxia and low nutrient supply (Alfarouk et al., 2014). Cancer mutations can
directly affect metabolic enzymes such as succinate dehydrogenase (SDH) and fumarate
hydratase (FH) – which are essential for the tricarboxylic acid (TCA) cycle (Tomlinson et al., 2002). Another relevant
enzymatic mutation is found in isocitrate dehydrogenase 1 (IDH1). Mutant IDH1
has been identified in low-grade glioma and acute myeloid leukemia (AML) (Balss et al., 2008; Borger et al., 2012). In contrast to wild
type IDH – which converts isocitrate to ?-ketoglutarate – these mutants use ?-ketoglutarate
as substrate to form 2-hydroxyglutarate (2-HG). 2-HG accumulation has been
proposed to drive oncogenesis via redox stress induction (Dang et al., 2009). Moreover, 2-HG is a
competitive inhibitor of ?-ketoglutarate dependent dioxygenases; thus, 2-HG
production results in genome-wide change of histone and DNA methylation (Xu et al., 2011). Indeed, IDH-driven
malignancies display prominent CpG island hypermethylation, similar to SDH and
FH defective cancers (Lu et al., 2012; Pavlova & Thompson, 2016). These mutations were
associated with hereditary forms of cancer and highlight the importance of
metabolism in neoplastic transformation. While alterations in glucose
metabolism and its products were found and affirmed early (Hay, 2016; Warburg, 1956), other metabolic
molecules are emerging and establishing in importance (Cairns, Harris, & Mak, 2011; Cairns & Mak,
2016). An example
is acetate (Schug, Vande Voorde, & Gottlieb, 2016), which is obtained
from pyruvate and converted to acetyl-CoA, that can be used for energy
production, for lipid biosynthesis and is an epigenetic regulator in histone
acetylation (Cairns & Mak, 2016). Glutamine, also, is an important
substrate for energy production, catabolism and glutathione synthesis and is
found relevant in cancer cells metabolism (Cairns & Mak, 2016). The lipids
are involved for the most part in membrane synthesis, thus ATP-dependant citrate
lyase (ACLY) and fatty acid synthase (FASN), two enzyme involved in lipid
biosynthesis, are necessary for sustained cell proliferation in cancer (Danhier et al., 2017). Moreover, it is
notable that products of metabolism such as S-adenosylmethionine (SAM) – from
the serine catabolism -, NAD+ and FAD are involved in epigenetic
modifications: SAM is a methyl group donor for methyl marks in mRNA, while NAD+
and FAD are cofactor respectively for sirtuins – which removes acetyl marks
from histone and nonhistone proteins – and for a lysine-specific demethylase
LSD1 (Pavlova & Thompson, 2016).

 

2.2. Glucose metabolism and its role
in tumours

The
main metabolic pathways interested in gathering energy are the carbohydrate
catabolism reactions. Polysaccharides such as amid and glycogen and
disaccharides as sucrose and lactose represent the main sugar intake in our
diet. Many enzymes break down these molecules into three monomers: glucose,
lactose and fructose. Of those, glucose is the more important, since it is the
initial substrate of the pentose phosphate pathway (whose products are required
for fatty acid biosynthesis, nucleic acid biosynthesis and amino acid
biosynthesis), of the hexosamine pathway (which functions as a cellular
nutrient sensor) and, of course, glycolysis – which is core to the entire cell metabolism.

Glycolysis is an oxygen independent
metabolic pathway that converts glucose into pyruvate with a net profit of two
molecules of Adenosine triphosphate (ATP) and two of reduced nicotinamide
adenine dinucleotide (NADH). Depending on oxygen availability, pyruvate has two
possible destinies: (1) in aerobic conditions pyruvate is oxidized to acetyl-CoA
and enters the tricarboxylic cycle in mitochondria, where it provides
substrates for oxidative phosphorylation (OXPHOS); or (2) in anaerobic
conditions pyruvate is reduced to lactate (lactic fermentation). Differences
dwell both in speed and yield; although glycolysis produces less ATP than OXPHOS
(36:2 molar ratio), the speed of the process is up to 100 times quicker in the
latter (Cairns, Harris, & Mak, 2011), making it more suitable for fast
energy production. Early studies found that cancer cells convert glucose into
lactate even under aerobic conditions, a phenomenon named “Warburg effect” after
its discoverer Otto Warburg, while oxidative phosphorylation (OXPHOS) was
supposed to be damaged and/or inactivated. The relative
increase in glycolysis exhibited by cancer cells under aerobic conditions was
actually mistakenly interpreted as evidence for damage to respiration instead
of alteration in the regulation of glycolysis (Hay, 2016; Koppenol, Bounds, & Dang, 2011). As a matter of fact, higher rates of glucose uptake and glycolysis happens
despite the occurrence of OXPHOS in proliferating cancer cells (Hay, 2016).

Glucose metabolic alterations are
interconnected with oncogenic signalling.
The Warburg effect has been found to be determined by several entwined
pathways and molecules, such as the PI3K/AKT pathway, hypoxia inducible factor
(HIF), p53, MYC and the AMP-activated protein kinase (AMPK)-liver kinase B1
(LKB1) pathway (Cairns et al., 2011).  To enhance its disposability of glucose, cancer
cells reprogramme their glucose metabolism and uptake. Even though a universal
pattern of metabolic alterations has not been found, an affirmed relationship
between metabolism and well-known oncogenes has been established (Hay, 2016). The hypoxia inducible
factor 1 (HIF1) transcription factor is found to enhance glucose uptake by
increasing the expression of glucose transporter GLUT1 and of the enzyme
hexokinase-2 (HK2), responsible of glucose phosphorylation (Hay, 2016). GLUT1 is critical for
cancer cells: it can import glucose into the cell even at low extracellular
levels for glycolysis. HIF1 activity is found both in hypoxic condition and as
the result of other oncogenic signalling pathways, such as
phosphatidylinositide 3-kinases (PI3K) (Cairns et al., 2011). p53 promote the
expression of TIGAR (TP53-induced glycolysis and apoptosis regulator), a
fructose-2,6-bisphosphatase enzyme homologous, which suppresses glycolysis in favour
of NADPH production by the pentose phosphate pathway (Hay, 2016; Schulze & Harris, 2012). Also, TIGAR enzymatic
activity heightens fructose-6-phosphate (F6P) levels, F6P can be reverted to
glucose-6-phosphate (G6P) and therefore inhibits HK2 activity (Hay, 2016). Gain-of-function
mutant TP53 is also related to increased level of GLUT1 at the plasma membrane,
which affects RHOA-Rho-associated protein kinase (ROCK) signalling (Hay, 2016).