Page 32 - Read Online

Nguyen et al. Cancer Drug Resist 2018;1:126-38 I http://dx.doi.org/10.20517/cdr.2018.08 Page 131

methylation and they are inhibited by the accumulation succinate, the by-product of these enzymes.

One example of the role of glutamine-derived α-ketoglutarate in the regulation of histone and DNA meth-
ylation is the neomorphic mutations in IDH1/2 [60,61] . Moreover, loss-of-function mutations of succinate
dehydrogenase (SDH) increase cellular succinate level, which inhibits DNA demethylation and contribute
to tumorigenesis [62,63] . Finally, low glutamine in the core region of solid tumors led to histone hypermethyl-
ation due to decreased α-ketoglutarate level, resulting in cell dedifferentiation and therapeutic resistance in
[64]
melanoma cells . Accordingly, glutamine metabolism plays a role in gene expression through the contri-
bution of α-ketoglutarate and succinate to chromatin structure modification.

GLUTAMINE ADDICTION IN CANCER
Due to the high demand of cancer cells for glutamine, glutamine metabolism is highly regulated in order
to maintain cellular biosynthesis and cell growth. Thus, the machinery which regulates glutamine metabo-
lism, needs to be very efficient to increase the cellular access to glutamine. The first mechanism to enhance
glutamine acquisition is to induce glutamine uptake. Different glutamine transporters are known, espe-
cially SLC1A5/ASCT2 which is controlled by c-myc or E2F. SLC1A5 is highly expressed in triple-negative
[65]
breast cancer patients, correlating with poor survival in tumor-bearing mice . Besides, other transporters
such as SLC38A1/SNAT1 and SLC38A2/SNAT2 can compensate for the depletion of SLC1A5/ASCT2 to
[66]
contribute to glutamine uptake .

The expression and activity of glutaminolytic enzymes, GLS and GDH, are also tightly regulated. GLS is
inhibited by its product glutamate or by inorganic phosphate. Sirtuin 5 (SIRT5), which is overexpressed in
lung cancer, decrease the succinylation of GLS to regulate ammonia production and ammonia-induced au-
tophagy . The transcription factor c-myc induces the expression of GLS through the repression of miR-23a
[67]
and miR-23b62. Furthermore, additional mechanisms are reported to regulate GLS, such as RNA-binding
protein regulation of alternative splicing [68,69] or protein degradation through the ubiquitin ligase complex
[70]
APC/C-Cdh1 during cell cycle progression .
Similar to GLS, GDH expression and activity are controlled by different effectors. GDH is allosterically
regulated by activators like ADP and leucine, or by inhibitors like ATP, GTP and palmitoyl-CoA [71-73] . At
the level of post-translational modification, the sirtuin SIRT4 ADP-ribosylates and downregulates GDH
in beta-pancreatic cells, thereby decreasing insulin secretion in response to amino acids during calorie-
[74]
sufficient conditions . When the extracellular glutamine level is limited, some cancer cell lines are able to
induce GS expression in order to escape from glutamine deficient-induced cell death. GS has been found to
be overexpressed in some cancers, such as breast cancer or glioblastoma, promoting cell proliferation [40,75] .
GS transcription is activated by different oncogenic pathways, such as PI3K-PKB-FOXO pathway , c-
[76]
[77]
[78]
myc , and Yap1/Hippo pathway . Moreover, GS is inactivated by extracellular glutamine because the
presence of glutamine induces GS acetylation by p300/CBP protein, facilitating its ubiquitination and pro-
teasomal degradation [79-81] .
Glutamine addiction appears when cancer cells undergo cell death in conditions of glutamine limitation
or when glutamine metabolism is inhibited. Many cancer cells which rely on glutamine catabolism for
building blocks and energy have been reported to be addicted to glutamine [33,82-84] . Glutamine-addicted
cells exhibit a decreased survival, or even undergo apoptotic cell death, associated with an increased in
DNA damage, an overproduction of ROS or a decreased reduced/oxidized glutathione (GSH/GSSG) ratio.
In this context, the oncogenic transcription factor c-myc plays a key role in the induction of glutamine
addiction [18,33] . Together, these results suggested that this phenotype could be exploited as cancer therapy
through the use of inhibitors of glutaminolytic enzymes or treatment which induce glutamine depletion