Page 28 - Read Online

Nguyen et al. Cancer Drug Resist 2018;1:126-38 I http://dx.doi.org/10.20517/cdr.2018.08 Page 127

cancer cells to a changing environment. Cancer cells harbor oncogenic mutations, leading to an increase in
nutrient uptake, and altering their metabolism to support anabolic processes for cell growth and prolifera-
tion.

Uptake
In order to guarantee a rapid cell proliferation, cancer cells first need to increase the uptake of nutrients
from the extracellular environment. Glucose and glutamine are two main nutrients that cancer cells up-
take from extracellular environment. Cancer cells become easily “addicted” to glucose and glutamine, as
their withdrawal can induce cell death. Through the catabolism of glucose and glutamine, the cells produce
both carbon intermediates as building blocks and reducing power for macromolecules production and
[2]
ATP generation. The increase in glucose consumption by cancer cells was first described by Warburg . He
saw that cancer cells consume 10 times more glucose than non-proliferating normal cells, and they convert
glucose to lactate even in the presence of oxygen and fully functioning mitochondrial respiration. The so-
called “Warburg effect” (or aerobic glycolysis) has become a well-known and common metabolic pheno-
[3]
type allowing tumors to fulfil the energetic requirement for cell growth . Positron emission tomography
(PET)-based imaging of the high uptake of a radioactive fluorine-labeled glucose analogue 18F-fluorode-
oxyglucose (18F-FDG) by cancer cells is used as an imaging tool for the detection of several cancers and
[4]
for the monitoring of treatment response . Cancer cells acquire oncogenic alterations to increase glucose
uptake, independently of external stimuli. For instance, PI3K/AKT pathway promotes both the expression
of glucose transporter GLUT1 mRNA and the translocation of GLUT1 protein from endomembranes to
[5,6]
the cell surface . Furthermore, AKT potentiates the activity of hexokinase and phosphofructokinase en-
zymes, which catalyse rate-limiting steps of glycolysis, in order to induce glucose consumption to branch-
[7-9]
ing pathways . Additionally, GLUT1 mRNA expression is upregulated by Src or Ras protein, mostly in
[10]
the presence of two enhancer elements in the gene . Thus, oncogenic signaling pathways, which are often
upregulated in cancer, share also another common point to induce glucose import.
[11]
High glutamine demand was first described by Eagle , when he saw that cultured HeLa cells required 10
to 100 times more of glutamine than any other amino acid. Not only as carbon source, glutamine is also a
nitrogen source for de novo biosynthesis of different nitrogen-containing building blocks, such as purine
and pyrimidine nucleotides, glucosamine-6-phosphate, and nonessential amino acids. Moreover, glutamine
participates in the uptake of essential amino acids from extracellular environment. For example, leucine
is imported through the plasma membrane by the amino acid antiporter LAT1/SLC7A5 in coupling with
[12]
an efflux of glutamine . Indeed, LAT1/SLC7A5 expression has been reported to be increased in several
cancer types [13,14] . Due to the high demand of glutamine, this amino acid is also used for imaging based on
18F-labeled glutamine tracers in preclinical and clinical studies, especially when the use of 18F-FDG is not
feasible, like in the brain [15,16] . The mechanisms of glutamine uptake regulation are still being identified.
The principal regulator of glutamine utilization is the transcription factor c-myc, which is often upregu-
lated in proliferating cells [17,18] . Indeed, c-myc induces the transcription of glutamine transporters, such as
SLC1A5/ASCT2, and also promotes the expression of glutamine-catabolized enzymes such as glutaminase
1 (GLS1) and carbamoyl-phosphate synthetase 2 - aspartate transcarbamylase - dihydroorotase (CAD), in
order to encourage glutamine uptake by converting glutamine to glutamate [19-21] . In addition, glutamine up-
take can be negatively regulated by retinoblastoma (Rb) tumor suppressor family, whose deletion increases
[22]
glutamine uptake via the E2F-dependent upregulation of SLC1A5/ASCT2 and GLS1 . Thus, glutamine
consumption is supported by the activity of c-myc and E2F transcription factors which regulate cell cycle,
to ensure the cellular access to glutamine for DNA replication.

Metabolic intermediates for biosynthesis
Despite the original idea of Warburg that aerobic glycolysis was originated as a consequence of mitochon-
[2]
drial dysfunction, subsequent studies showed that mitochondria of cancer cells are still functional and able
to conduct oxidative phosphorylation. To adapt to a rapid proliferation, cancer cells need building blocks,