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Page 132 Nguyen et al. Cancer Drug Resist 2018;1:126-38 I http://dx.doi.org/10.20517/cdr.2018.08

like L-asparaginase.

On the contrary, some cell types show glutamine independence due to the expression of GS. Indeed, glio-
ma cells can synthetize glutamine from glutamate through the activity of GS, maintaining the cell prolif-
[85]
eration during glutamine deprivation . Also, those cells use glucose as a source for TCA cycle anaplerosis,
which can sufficiently provide α-ketoglutarate for glutamate and glutamine synthesis. However, the source
of the free ammonia necessary for glutamine synthesis is not clear. Alternatively, some cell types can adapt
to glutamine withdrawal using asparagine [45,86] . Asparagine is indeed playing a role in the exchange of ex-
[87]
tracellular amino acids, especially serine, arginine and histidine . Despite that asparagine is synthetized
from glutamine through asparagine synthetase, how cancer cells adapt their metabolic needs during gluta-
mine deprivation remains to be elucidated.

GLUTAMINE METABOLISM AND MTORC1 PATHWAY
Glutamine metabolism and mammalian target of rapamycin complex 1 (mTORC1) pathway have a tight
connection through different mechanisms. The activation of mTORC1 by glutamine and other amino ac-
ids is mediated by the Rag GTPase pathway. In addition, glutamine plays a role as the efflux solute for the
import of leucine which supports glutamine to activate mTORC1 through glutaminolysis. Moreover, gluta-
mine and leucine cooperate to produce α-ketoglutarate through glutaminolysis, which ultimately activates
mTORC1. Indeed, short-term glutaminolysis induces mTORC1 lysosomal translocation and activation
via the Rag GTPase, then inhibiting autophagy and promoting cell growth . Moreover glutaminolysis-
[88]
mediated mTORC1 activation required prolyl hydroxylase (PHD) enzymatic activity in a HIF-independent
[89]
manner . Those evidence highlight the role of glutaminolysis-PHD-mTORC1 axis in cancer growth. Be-
sides, glutamine stimulates lysosomal translocation and activation of mTORC1 via the small GTPase ARF1
and v-ATPase in RagA and RagB knockout cells without Ragulator contribution .
[90]

In agreement with this positive connection between glutaminolysis and mTORC1, FOXO-mediated expres-
[76]
sion of GS inhibits mTOR signaling by blocking its lysosomal translocation . This mechanism is impor-
tant for maintaining autophagy during nutrient deprivation. Hence, mTORC1 sense glutamine availability
in both directions: when glutamine is available, mTORC1 is activated via α-ketoglutarate production; but
mTORC1 is inactivated when glutamine production is triggered.

The connection between glutamine metabolism and mTORC1 present additional connection branches, as
[91]
glutamine also plays a role in autophagy-induced mTORC1 restoration during amino acid starvation .
Thus, glutamine recycling, supported by autophagy, is sufficient to reactivate mTORC1 under restrictive
conditions.

However, and paradoxically, long-term glutaminolysis activation during nutritional restriction induces an
[92]
unbalanced activation of mTORC1 during nutrient deprivation and promotes apoptosis . This type of
metabolic-induced cell death is called “glutamoptosis”, which supports a tumor suppressor role of gluta-
mine metabolism and mTORC1 (normally known as pro-proliferative inducers) during nutritional imbal-
ance. During glutamoptosis, mTORC1-mediated inhibition of autophagy leads to the accumulation of the
autophagic cargo protein sequestosome1/p62 (SQSTM1/p62). Then SQSTM1/p62 interacts with Caspase
8 and activates it to trigger apoptosis. Strikingly, the inhibition of mTORC1 by rapamycin promoted cell
survival upon amino acid starvation, which could partially explain the resistance to rapamycin treatment
observed in some tumor cells.

Conversely, mTORC1 can regulate glutamine metabolism via different mechanisms. GLS and GDH are
both regulated by mTORC1 pathway. Mechanistically, mTORC1 inhibits the transcription of SIRT4 by
degrading its activator CREB2 (cyclic adenosine monophosphate responsive element-binding 2), thereby
activating GDH [74,93,94] . Also, mTORC1 activate GLS through S6K1/eIF4B-dependent mRNA translation