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Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Málaga, Spain
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ABSTRACT |
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 TOP ABSTRACT Why are tumors highly...Changes in host glutamine...Glutamine transport and...Therapeutical, nutritional and...Current and future trendsLITERATURE CITED |
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KEY WORDS: • glutamine • cancer • glutaminase • glutamine synthetase • transglutaminase
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Why are tumors highly glutaminolytic? |
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TOPABSTRACTWhy are tumors highly...Changes in host glutamine...Glutamine transport and...Therapeutical, nutritional and...Current and future trendsLITERATURE CITED |
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). Mider (1951)
showed that tumors
assimilate not only the nitrogen from the diet, but also the nitrogen
from host proteins, raising the concept of tumors as "nitrogen
traps," actively competing with the host for nitrogen compounds
(Landel et al. 1985
). Tumors use the incorporated amino
acids for both oxidation and protein synthesis (Shapot 1979
).
Because glutamine is the most abundant amino acid in the body and the
main vehicle for circulation of ammonia in a nontoxic form
(Medina et al. 1992
), some authors consider that tumors
behave indeed as "glutamine traps" (Klimberg and McClellan 1996
,Souba 1993
). The highly tumorigenic human
breast cancer cell line, TSE cells, exhibit up-regulation of
glutamine synthetase protein and mRNA levels and a decline in
intracellular glutamine content upon chronic glutamine deprivation
(Collins et al. 1997
). The concept of tumor as a
"glutamine trap" has sometimes been misunderstood and has been
severely criticized. For example, it has been reported that glutamine
oxidation is unlikely in hypoxic or anoxic tumor because oxygen is
required for the reoxidation of essential coenzymes (Kallinowski et al. 1987
). However, the main basis for this criticism is the
incorrect assumption that glutamine is oxidized mainly by tumor cells.
This does not seem to be true; in fact, tumors often waste energy and
metabolic substrates. When Ehrlich ascites tumor cells are perfused
with a continuous input of 0.5 mmol glutamine and steady state is
reached, there is a perfect stoichiometry of one glutamate released per
glutamine taken up (Segura et al. 1989
). This behavior
of tumors is also observed with other energy substrates, i.e., when 5
mmol glucose is used as a substrate, there is a perfect stoichiometry
at steady state of two lactate molecules released per molecule of
glucose taken up (Segura et al. 1989
). Thus, it can be
concluded that tumors are powerful energy dissipaters, consistent with
the nonequilibrium thermodynamics developed by Prigogine (1980)
. There is experimental evidence to support tumor cell
mitochondrial respiratory chain as an intracellular dissipative
structure
(IDS),3
as espoused by Ji (1985)
. He defined IDS as
disequilibrium distributions of chemicals inside cells that are
maintained through a dissipation of free energy. The experimental
evidence for this observation is termed a "noncommutativity test."
A characteristic property of dissipative structures, not observed in
equilibrium or near-equilibrium systems, is the possibility of
successive metabolic bifurcations, which may drive the system to very
different final states, depending on the order of substrate addition.
In Ehrlich cells incubated with glucose and glutamine, the oxidative
states of mitochondrial cytochromes at the end of incubation were very
different, depending on the order of addition of glucose and glutamine.
These results support Ji’s IDS hypothesis (Medina and Núñez de Castro 1988
).
Tumor cells are highly variable in their energy requirements. Hence,
these cells are "efficacious" but "nonefficient" energy
systems. They are "efficacious" in the sense that they are able to
utilize energy inputs from very different sources and under very
different environmental circumstances. They are not "efficient" in
the sense that they seem to waste most of the energy inputs without any
apparent profit. This apparent wasteful spreading of energy has been
theoretically justified on the basis of the quantitative principles of
metabolic control theory (Crabtree and Newsholme 1985
).
In branded metabolic pathways, these authors demonstrated that if the
flux through a metabolic branch is far higher than the flux through
another branch, then the pathway with a small flux has a very high
sensitivity to the modulators of the small flux. Both glycolysis and
glutaminolysis represent wide metabolic branches, whereas the branches
directed to macromolecule synthesis represent the small ones. In
conclusion, these authors suggest that high rates of glycolysis and
glutaminolysis are needed not for energy or precursor provision per se
in cancer cells. Moreover, they are required for the pathways involved
in macromolecule synthesis for specific regulators, thereby permitting
high rates of proliferation when required.
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Changes in host glutamine metabolism upon cancer onset |
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TOPABSTRACTWhy are tumors highly...Changes in host glutamine...Glutamine transport and...Therapeutical, nutritional and...Current and future trendsLITERATURE CITED |
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, Márquez and Núñez de Castro 1991
, Quesada et al. 1988a, 1996
). There
is a net flux of glutamine from host to tumor, which is possibly due to
a net production of glutamine by host tissues as a result of an
increase in the glutamine synthetase (GS)/glutaminase (GA) ratio. Our
group studied this topic extensively in the tumor model of Ehrlich
cells growing in the peritoneum of mice. The changes in the GS/GA ratio
are evident both at mRNA and enzyme activity levels as early as 24 h after tumor implantation in kidney and liver (Aledo et al. 2000
, Quesada et al. 1988b
). On the contrary, in
spleen, an important organ of the immune system, there is a transient
increase of GA mRNA and activity levels (Aledo et al. 1998
). These results agree extensively with those reported by
other authors in other tumor models (Medina et al. 1992
,
Souba 1993
). |
Glutamine transport and metabolism by tumor cells |
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TOPABSTRACTWhy are tumors highly...Changes in host glutamine...Glutamine transport and...Therapeutical, nutritional and...Current and future trendsLITERATURE CITED |
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), but fatty acids also
interfere with glutamine metabolism (Medina et al. 1988a
).
Because glutamine metabolism takes place in the mitochondria, it must
be transferred from extracellular medium through specific plasma
membrane and inner mitochondrial membrane transporters. Plasma membrane
glutamine transport is reviewed by Bode (2001)
in this
publication. As a general rule, malignant cells transport glutamine
across their plasma membranes at a faster rate than their nonmalignant
counterparts (Espat et al. 1995
, Medina et al. 1991 and 1992
, Souba 1993
). After glutamine
gains access to the cytoplasm, it must be transported into
mitochondria. Kovacevic et al. (1970)
first postulated
the existence of a neutral uniport mechanism for glutamine uptake into
liver mitochondria. Because the mitochondrial transport of metabolites
is usually 1–2 orders of magnitude faster than the plasma
membrane–related transport, special problems arise in transport
studies conducted with isolated mitochondria. To allow transport
measurements without any interference by the mitochondrial glutamine
metabolism, our group used native vesicles isolated from mitochondrial
inner membrane to characterize the mitochondrial glutamine transport
system of Ehrlich ascites tumor cells. Data confirm the existence of a
specific mitochondrial transport system with high capacity for
L-glutamine, showing cooperativeness and strong inhibition
by the thiol reagent p-chloromercuriphenylsulfonic acid and
the glutamine analog L-glutamate-
-hydroxamate
(Molina et al. 1995
).
In the mitochondria, glutamine is acted upon by glutaminase, an enzyme
requiring high phosphate concentrations to be fully active. The high
concentrations of inorganic phosphate found in the mitochondria of
tumor cells (Medina et al. 1988b
) could explain the high
activity of tumor glutaminase in vivo. In fact, experimental evidence
supports the correlation of glutaminase activity with the extent of
malignant proliferation (Medina et al. 1992
,
Souba 1993
). Tumor glutaminase reaches a maximum of
expression and activity immediately before the maximum proliferation
rate (Aledo et al. 1994
, Gómez-Fabre et al. 2000
).
Although Huang and Knox (1976)
partially purified the
enzyme from a mammary carcinoma, our group was the first one reporting
a tumor glutaminase purification to homogeneity (Quesada et al. 1988b
). Afterward, our own group provided two alternative
purification procedures that increased yield and decreased purification
time (Segura et al. 1995
). Purified Ehrlich ascites
tumor cell glutaminase has been studied extensively and characterized
both kinetically and topographically (Aledo et al. 1997
,
Campos et al. 1998
, Quesada et al. 1988b
).
On the other hand, glutamine synthetase has classically been considered
as a "dispensable" enzyme for tumors (Medina et al. 1992
). However, as previously mentioned, at least some tumors
exhibit glutamine synthetase up-regulation as an adaptive response
to glutamine depletion (Collins et al. 1997
).
|
Therapeutical, nutritional and pharmacologic aspects |
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TOPABSTRACTWhy are tumors highly...Changes in host glutamine...Glutamine transport and...Therapeutical, nutritional and...Current and future trendsLITERATURE CITED |
|---|
, Souba 1993
).
Nutritional and pharmacologic aspects of glutamine are covered by other
reviews in this publication. There is increasing evidence supporting a
protective role for glutamine supplementation in enteral or total
parenteral nutrition (Amores-Sánchez and Medina 1999
). In relation to cancer, it seems that a supplementation
of glutamine in the diet may be beneficial for several reasons. Tumor
progression is associated with an avid consumption of host glutamine by
tumor cells and a depression in the activity of natural killer cells
due to a decrease in glutathione concentrations in these cells.
Therefore, dietary supplementation of glutamine could have the
beneficial effect of restoring the levels of glutathione inside natural
killer cells; at the same time, however, it could have the deleterious
effect of feeding the tumor. However, because glutamine consumption by
tumors is almost absolutely dissipative, an increase in the growth rate
of the tumor due to this process should not be expected (Austgen et al. 1992
, Medina and Núñez de Castro 1990
). In fact, there are experimental data that seem to
indicate that a dietary supplement diminishes tumor growth by restoring
the function of natural killer cells and improves protein metabolism of
the host or patient (Fahr et al. 1994
, Yoshida et al. 1995
).
Additionally, an oral supplement of glutamine can increase the
selectivity of antitumor drugs (Cao et al. 1999
,
Decker-Baumann et al. 1999
, Miller 1999
)
by protecting the patient from oxidative damage through an increase in
glutathione contents (Rouse et al. 1995
). Several groups
have shown that glutamine can also protect against oxidative damage
induced by radiotherapy (Jensen et al. 1994
,
Miller 1999
, Yoshida et al. 1995
).
However, there is no consensus on the usefulness of glutamine
supplementation for cancer patients. For instance, a recent
double-blind, randomized study on glutamine supplementation in
cancer patients receiving chemotherapy concluded that glutamine did not
have a significant effect on either tumor response or secondary effects
of chemotherapy (Bozzetti et al. 1997
).
|
Current and future trends |
|---|
|
TOPABSTRACTWhy are tumors highly...Changes in host glutamine...Glutamine transport and...Therapeutical, nutritional and...Current and future trendsLITERATURE CITED |
|---|
used a cDNA
library from human colon adenocarcinoma cell line HT-29, and
Gómez-Fabre et al. (2000)
used a cDNA library from
human breast cancer cell line ZR75–1. Interestingly, their
tissue-specific expressions are different. Two of the isoforms
identified by Elgadi et al. (1999)
show high homology
with rat kidney-type glutaminase, and a third isoform of
glutaminase, previously identified by Imbert et al. (1996)
, is expressed only in cardiac and skeletal muscle. On
the other hand, the glutaminase isoform cloned from ZR75–1 cells seems
to be a liver-type glutaminase, with high expression levels in
human liver and lower expression in pancreas and brain
(Gómez-Fabre et al. 2000
). This result is in sharp
contrast with the view that kidney-type glutaminase is the isoform
expressed in all tissues with glutaminase activity with the exception
of postnatal liver. Furthermore, because Elgadi et al. (1999)
found that one of the kidney-type isoforms is the
predominant glutaminase expressed by the TSE breast carcinoma cell
line, the implications of a possible expression of both kidney- and
liver-type glutaminases in breast cancer should be analyzed in the
immediate future. Once the cloning of tumor glutaminase has been achieved, the future trends in this research area can be easily predicted. One of the main goals should be to provide further insight into tumor glutaminase gene expression and regulation by systematic studies of their promoter regions and by the identification of proteins interacting with tumor glutaminase.
A second important new development in this research area has been the
successful inhibition of glutaminase expression by antisense mRNA
(Lobo et al. 2000
). Ehrlich ascites tumor cells
transfected with a vector containing a 0.28-kb antisense segment of the
C-terminal region of rat kidney-type glutaminase showed
impairment in their growth rate and plating efficiency, as well as
shortage in glutaminase protein and activity levels and remarkable
changes in their morphology. Furthermore, these transfected cells lost
their tumorigenic capacity in vivo, thus providing new ways for
possible therapeutic applications. It can be anticipated that this will
be a very active area of research in the near future.
Finally, a new interest is emerging for tissue transglutaminases.
Four human transglutaminase genes have been identified (Dubbink et al. 1998
). Tissue transglutaminase is a marker of apoptosis
and has been postulated to play a role in cell adhesion, metastasis and
extracellular matrix assembly (Hettasch et al. 1996
,
Rittmaster et al. 1999
). Tissue transglutaminase-2
expression levels seem to correlate with drug resistance in cancer
cells (Han and Park 1999
, Mehta 1994
). On
the other hand, tissue transglutaminase-4 is prostate specific and its
expression is inhibited in most metastatic prostate cancers (An et al. 1999
, Rittmaster et al. 1999
). Very
recently, it has been shown that tissue transglutaminase is directly
involved in wound healing and angiogenesis (Haroon et al. 1999
). A possible involvement of tissue transglutaminase in
tumor angiogenesis should be evaluated. Furthermore, the tumor
specificity and the positive or negative involvement of the different
tissue transglutaminases in tumor progression will warrant future
efforts in this important area of research.
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FOOTNOTES |
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2 Supported in part by grants SAF98–0150 from
CICYT and 1FD97–0693 from the FEDER Program of the EU.
3 Abbreviations used: GA, glutaminase; GS,
glutamine synthetase; IDS, intracellular dissipative structure.
|
LITERATURE CITED |
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|
TOPABSTRACTWhy are tumors highly...Changes in host glutamine...Glutamine transport and...Therapeutical, nutritional and...Current and future trendsLITERATURE CITED |
|---|
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