1 Division of Nephrology-Hypertension and 2 Program in Molecular Pathology, Department of Medicine, University of California, San Diego, and Veterans Affairs Medical Center, La Jolla, California 92161
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ABSTRACT |
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Nitric oxide (NO)
has been described to exert cytostatic effects on cellular
proliferation; however the mechanisms responsible for these effects
have yet to be fully resolved. Polyamines, conversely, are required
components of cellular proliferation. In experimental models of
inflammation, a relationship between these two pathways has been
suggested by the temporal regulation of a common precursor, arginine.
This study was undertaken to determine the effects NO and the NO
synthase (NOS)-inducing cytokines, tumor necrosis factor- (TNF-
)
and interferon-
(IFN-
), exert on polyamine regulation. The
transformed kidney proximal tubule cell line, MCT, maintains high
constitutive levels of the first polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). NO donors markedly suppressed ODC activity in MCT and all other cell lines examined. TNF-
and IFN-
induction of NO generation resulted in suppressed ODC activity, an
effect prevented by the inducible NOS inhibitor
L-N6-(1-iminoethyl)lysine
(L-NIL). Dithiothreitol reversal
of NO-mediated ODC suppression supports nitrosylation as the mechanism
of inactivation. We also evaluated polyamine uptake, inasmuch as
inhibition of ODC can result in a compensatory induction of polyamine
transporters. Administration of NO donors, or TNF-
and IFN-
,
suppressed
[3H]putrescine uptake,
thereby preventing transport-mediated reestablishment of intracellular
polyamine levels. This study demonstrates the capacity of NO and
inflammatory cytokines to regulate both polyamine biosynthesis and transport.
antizyme; inflammation; nitrosylation; ornithine decarboxylase; proliferation; tumor necrosis factor-; interferon-
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INTRODUCTION |
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ARGININE IS A PRECURSOR substrate for two well-described metabolic pathways, the production of nitric oxide (NO) by NO synthase (NOS) and the production of urea and ornithine by arginase. NO has been well documented as a cytostatic agent (1, 12, 26, 37, 45, 46, 48). Ornithine is the precursor of polyamines through the first rate-limiting enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC). Polyamines (putrescine, spermidine, and spermine) are required components for entry into and progression of the cell cycle (3) and as such play an important role in proliferation. In inflammatory models of experimental glomerulonephritis and wound healing these two arginine-based pathways are temporally regulated (2, 11, 25). The production of NO from arginine by inducible NOS (iNOS) is an early phase response, whereas arginine is diverted to proliferative and extracellular matrix production pathways in the later repair phase response. Administering a NOS inhibitor, NG-monomethyl-L-arginine, in experimental glomerulonephritis increases both the magnitude and rapid onset of the repair phase response (11). Thus models of inflammation suggest an interrelationship of arginine metabolic pathways to maintain the correct temporal relationships between such pathways. As NO is not an effective arginase inhibitor (for review, see Ref. 24), we speculated that NO may modulate the proliferative response in the early phase of inflammation by suppressing ODC. ODC requires a cysteine in its active center for full enzymatic activity. NO has been shown to modulate the activity of several enzymes through nitrosylation of cysteines (14-16, 36, 43, 44).
Along with polyamine biosynthesis by ODC, cells can also acquire polyamines from their external milieu. Induction of polyamine transport by arginine deprivation, but not ornithine deprivation (8), strengthens the position of arginine at the crux of both the polyamine and NO pathways. Polyamine transporters are stimulated by many of the same factors that induce ODC activity. In addition, polyamine transport can substitute for de novo polyamine biosynthesis under conditions such as ODC inhibition by difluoromethylornithine (DFMO) (8). Polyamine autoregulation occurs through the induction of antizyme, a protein that inhibits both ODC and polyamine transport, exemplifying the importance of polyamine transport in vivo. Taken together, these results illustrate the need to examine polyamine transport as well as biosynthesis when examining cellular access to polyamines.
In this study we have demonstrated that NO and the iNOS-inducing
cytokines tumor necrosis factor- (TNF-
) and interferon-
(IFN-
) can negatively regulate ODC activity and cellular polyamine uptake.
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MATERIALS AND METHODS |
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Chemicals
and
supplies. Sodium nitroprusside
(SNP),
S-nitroso-N-acetyl-D,L-penicillamine
(SNAP),
S-nitroso-L-glutathione
(GSNO), (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA NONOate),
(Z)-1-{N-methyl-N-[6-(N-methylammoniohexyl)amino]}diazen-1-ium-1,2-diolate (MAHMA NONOate), 3-morpholinosydnonimine (SIN-1), and
L-N6-(1-iminoethyl)lysine
(L-NIL) were purchased from
Alexis Biochemicals (San Diego, CA). TNF- and IFN-
were purchased
from Boehringer Mannheim (Indianapolis, IN). DFMO was kindly supplied
by Dr. E. Bohme, Hoechst Marion Roussel (Cincinnati, OH). All other
chemicals were purchased from Sigma (St. Louis, MO), unless otherwise noted.
Cell preparations. A transformed proximal tubule cell line, MCT (20), was used for all experiments, except where noted. Other cell lines examined include J774 (monocyte/macrophage), mMC (mouse glomerular mesangial) (50), ENDO (rat glomerular endothelial) (27), NIH/3T3 (fibroblast like), Ras/3T3 (Ras-transformed NIH/3T3) (49), and HT-1080 (fibrosarcoma). All cells were plated and allowed to grow to near confluence in DMEM (GIBCO/BRL, Grand Island, NY) supplemented with 5% calf serum (Gemini Bio-Products, Calabasas, CA). Cell lines are from American Type Culture Collection (ATCC; Manassas, VA), unless otherwise referenced.
ODC
activity. Cells were grown on 10-cm
culture plates, harvested by first washing with 10 ml ice-cold PBS,
placed in ice-cold ODC reaction buffer [10 mM Tris, pH 7.4, 2.5 mM dithiothreitol (DTT), 0.3 mM pyridoxyl-5-phosphate, and 0.1 mM
EDTA], and scraped, collected, and homogenized. Cell preparations
were then centrifuged at 30,000 g for
40 min at 4°C. The supernatant was collected and assayed for ODC
activity as previously described (35). Briefly, samples were aliquoted
at 250 µl in triplicate to large-bore glass tubes; reactions then
were started by the addition of 10 µM, 0.1 µCi
[14C]carboxyl-labeled
L-ornithine (NEN, Boston, MA) to
the cytosolic extracts. Tubes were capped with rubber stoppers fitted
with metabolic wells (KONTES, Vineland, NJ) containing 250 µl of
trapping agent (Solvable; Packard, Meriden, NJ). Incubations were for 1 h at 37°C. Reactions were stopped by injection of 200 µl 50% TCA
and allowed to equilibrate for an additional 1 h before the collection of metabolic wells and counting trapped
[14C]CO2
in a -scintillation counter.
Nitrite determination. Measurement of the NO end product nitrite production was used to assess relative values of NO released into the cell culture media. Nitrites were determined by the standard Greiss assay according to Green et. al. (17). Assays were carried out in 96-well plates and read in a Molecular Devices E max microplate reader at 550 nm.
Nitrate and nitrite determination. In assays where noted, nitrate was converted to nitrite by Escherichia coli nitrate reductase according to Bartholomew (5). The Greiss assay was then used to determine nitrite concentration, as above.
Transport
studies. Cells were grown in six-well
plates until nearly confluent. Wells were aspirated before addition of
1 ml DMEM containing 10 µM
[3H]putrescine (NEN)
at ~100,000 cpm/well. Uptake of
[3H]putrescine by MCT
cells was linear for >30 min (not shown). After the incubation
(uptake) reaction wells were washed three times with 3 ml PBS and cells
were lysed overnight in 1 ml 2 N NaOH and counted in a
-scintillation counter. Nonspecific binding (blank) was determined
as above, except the labeled
[3H]putrescine
addition was immediately terminated by aspiration and PBS washes.
Statistical evaluations. Variations between samples within groups were analyzed by ANOVA, with significance determined by Fisher's protected least-significant difference post hoc test. StatView software was used for these analyses.
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RESULTS |
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SNP suppresses ODC activity. We tested
the possibility that the NO donor SNP could suppress ODC activity in
the transformed kidney proximal tubule cell line MCT. The proximal
tubule is the primary source of arginine synthesis in the kidney (28)
and is known to have locally elevated arginase activity (29). These transformed cells also display constitutively elevated ODC activity. MCT cells were prepared for the ODC activity assay as described in
MATERIALS AND METHODS. SNP was added
to the homogenized cell preparation in the concentrations indicated in
Fig. 1A
at the start of the ODC assay reaction. SNP suppressed ODC activity in a dose-dependent fashion (Fig.
1A).
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We measured ODC activity in a number of established and transformed cell lines in the absence or presence of SNP (Fig. 1B). Primary cultures were not used because of their low inherent ODC activity. SNP markedly suppressed ODC activity in all cell lines examined.
NO donors suppress ODC activity. SNP
suppression of ODC activity was previously described by Blachier et.
al. (7) in a colon carcinoma cell line. To confirm that the suppressive
effects of SNP are due to NO rather than other by-products of SNP, we examined the effects of several other NO donors on ODC activity in MCT
cells. Three different redox groups of NO donors were represented: NONOates as NO · donors,
S-nitrosothiols (SNAP is a less toxic alternative to SNP, GSNO a physiological
S-nitrosothiol), which release
NO · and transfer nitrosonium
(NO+) to sulfhydryl centers
(44), and SIN-1 as a peroxynitrite
(OONO) generator. Cell
lysates were incubated for 1 h in the absence or presence of NO donors,
as indicated in Fig.
2A, before
the ODC assay. All NO donors displayed the capacity to suppress
ODC activity. Comparative NO end product generation by the various NO
donors is shown in Fig. 2B.
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Cytokine generation of NO suppresses ODC
activity. To determine if NO suppression of ODC
activity was of biological significance, we induced iNOS generation of
NO by TNF- (2.5 ng/ml) and IFN-
(50 U/ml) in MCT cells. Cytokine
stimulation significantly suppressed ODC activity (Fig.
3A).
Incubating cells with L-NIL (50 mM), an iNOS selective inhibitor, markedly reduced NO generation in
response to cytokines (Fig. 3B) and
consequently reduced the suppressive effects of NO induction on ODC
activity (Fig. 3A). Similar results were observed in the J774 cell line (not shown) or if
lipopolysaccharide (20 ng/ml) and IFN-
were used to induce NO
generation in MCT cells (not shown).
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Reversibility of ODC activity after NO
treatment. To determine if NO inhibition of ODC
activity involves nitrosylation of a sulfhydryl group, the effects of
the thiol reductant DTT were evaluated. Cells were harvested and
centrifuged as per MATERIALS AND
METHODS, except that DTT was omitted from the ODC
reaction buffer. Each sample was split and incubated in either the
absence (control) or presence of 0.5 mM MAHMA NONOate for 10 min at
room temperature. Varying concentrations of DTT, as shown in Fig.
4A, were
then added to the control and NO-treated samples for 10 min before
determination of ODC activity. MAHMA NONOate has a 1 min half-life,
thereby alleviating the need to separate the NO donor from the sample
by column purification before DTT addition. Increasing concentrations
of DTT resulted in increased enzymatic activity of ODC in samples
exposed to NO, relative to control samples in the presence of DTT alone
(Fig. 4A).
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The ability of DTT to reverse TNF-- and IFN-
-mediated ODC
suppression was also examined. Cytokines were administered to the cells
for varying lengths of time, as shown in Fig.
4B. Cells were then washed in PBS and
harvested in ODC reaction buffer without DTT and frozen. Thawed samples
were centrifuged, and the supernatants were aliquoted into reaction
tubes containing either 0.005 or 10 mM DTT for 15 min at room
temperature before assessment of ODC activity. The percent increase of
ODC activity from 0.005 to 10 mM DTT, relative to non-cytokine-treated
samples (0-h cytokine stimulation), is shown in Fig.
4B for each time point. DTT reversal of ODC activity in cells stimulated for 24 h with TNF-
and IFN-
was ineffective (not shown). However, there was a significant effect of
increased DTT concentration in cytokine-treated cells at 8, 10, and 12 h (Fig. 4B). A corresponding
increase in NO end product generation was observed at these time points
(Fig. 4C).
Polyamine transport is suppressed in the presence of
NO. Administration of DFMO, a potent specific inhibitor
of ODC, results in a compensatory increase in polyamine uptake (8). We
evaluated the effects of NO suppression of ODC activity on polyamine
transport to determine if non-antizyme-mediated inhibition of ODC
consequently results in compensatory induction of transport. Such an
effect could reestablish intracellular polyamine levels, negating
polyamine limitation as a mechanism by which NO could inhibit
proliferation. Although exceptions are known, most cells use a single
transporter for putrescine, spermidine, and spermine (41). Competition
studies in MCT cells suggest a single polyamine transporter (not
shown). [3H]putrescine
uptake by MCT cells was therefore used as an indicator of polyamine
transport in these studies. Transformed cells commonly display
increased polyamine uptake, and Fig.
5 demonstrates rapid transport
of [3H]putrescine into
MCT cells. The effects of DFMO require time to evolve. The presence of
DFMO did not change putrescine uptake relative to control values at 6 h, but increases were observed at 24 (105% increase over control) and
48 h (270% increase over control; not shown). In the presence of NO
donors a dose- and time-dependent suppression of putrescine uptake was
observed (Fig. 5). ENDO cells treated with SIN-1 gave similar results
(not shown).
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Cytokine administration suppresses polyamine
transport. To determine the biological significance of
NO suppression of polyamine transport we used TNF- and IFN-
to
induce iNOS generation of NO in MCT cells, as in Fig. 3. Cytokine
stimulation significantly suppressed
[3H]putrescine uptake
in MCT cells (Fig.
6A).
Incubating cells with L-NIL
(Fig. 6), an iNOS selective inhibitor, or
2,4-diamino-6-hydroxy-pyrimidine (DAHP) (not shown), an inhibitor of
the synthesis of the NOS cofactor tetrahydrobiopterin
(BH4), markedly reduced NO
generation in response to cytokines (Fig.
6B), but had little effect in
arresting cytokine-mediated suppression of
[3H]putrescine uptake
(Fig. 6A). TNF-
and IFN-
appear to act additively in suppressing polyamine transport (Fig.
6A).
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DISCUSSION |
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Limiting intracellular polyamine stores required for entry and progression through the cell cycle may prove a viable way of inhibiting proliferation. We have recently observed suppression of polyamine biosynthesis and transport in a transformed cell line through polyamine-independent induction of antizyme (39). Rapid depletion of putrescine and spermidine was observed with consequent inhibition of proliferation. Here we demonstrate that NO is capable of suppressing both polyamine biosynthesis and transport.
NO donors suppress the activity of the polyamine biosynthetic enzyme ODC in MCT cell extracts and in extracts of all cell lines examined (Fig. 1B), suggesting this effect is not cell type specific. NO donors differed in their ability to suppress ODC activity (Fig. 2A). Varying cellular responses to different redox forms of NO were previously noted (13). NO generated through cytokine induction of iNOS is also capable of suppressing ODC activity. This suppression is diminished in the presence of L-NIL, a selective inhibitor of iNOS (Fig. 3A). These data suggest that the effect on the enzyme is NO mediated and that cytokine-inducible levels of NO are capable of suppressing ODC activity.
Intracellular polyamine levels are autoregulated through translational
frameshift induction of a unique regulatory protein, antizyme (31).
Inhibition of polyamine biosynthesis occurs by antizyme binding to ODC
and suppressing ODC activity as well as rendering the enzyme
susceptible to proteolysis by the 26S proteosome in a
ubiquitin-independent manner (21, 34). A 30- to 60-min lag phase is
prerequisite to the onset of antizyme inhibition, with maximum
inhibition observed by 4 h in MCT cells (39). Suppression of ODC
activity by NO is rapid, as demonstrated in Fig.
1A, where the NO donor SNP is added
directly to the enzymatic reaction. These results are not temporally
compatible with those of antizyme. However, a rapid transition of
enzymatic activity could result from cysteine nitrosylation, which has
been shown to modulate the activity of several enzymes (14-16, 36,
43, 44). Active ODC is a homodimer containing a cysteine within the
active site at the dimer interface (10). A C360A mutation of this
cysteine in ODC has revealed this residue to be an absolute requirement for full activity (9, 10). Because of the rapid interchange of
enzymatic subunits under physiological conditions (10), this cysteine
may be subject to nitrosylation. DTT reversal of NO's inhibitory
effects on ODC activity (Fig. 4) is consistent with nitrosylation as
the mechanism of inhibition (19, 32). In our hands, TNF- and IFN-
stimulation of MCT cells results in an observable increase in iNOS
mRNA, as determined by Northern blotting (unpublished data), and an
increase in NO end product generation by 6 h (Fig.
4C). DTT reversal of
cytokine-mediated ODC suppression at 8, 10, and 12 h (Fig.
4B) is in temporal accord with these
observations. The ability of DTT to reverse ODC inhibition by TNF-
and IFN-
shortly after induction of NO generation suggests nitrosylation as an early event in this response. The ineffective reversal of ODC activity by DTT in cells stimulated for 24 h (not shown) implies that other cytokine-mediated mechanisms suppress ODC
activity by this later time point. We show here that cytokine-mediated suppression of ODC activity in cells treated for 24 h can be largely averted in the presence of the iNOS inhibitor
L-NIL (Fig. 3), suggesting that
NO may be required for induction of some of these other mechanisms.
Cytokines may additionally suppress ODC activity through NO-independent
mechanisms. The time frame and level(s) of cytokine regulation of ODC
activity require further investigation.
Suppression of polyamine transporters is a second function in the regulation of intracellular polyamines ascribed to antizyme (33, 47). It is this two-pronged mechanism of antizyme that distinguishes it from synthetic ODC inhibitors, such as DFMO. DFMO inhibition of ODC causes a compensatory induction of polyamine transporters, allowing polyamine uptake to substitute for de novo biosynthesis (8) (Fig. 5). In vivo, tumor cells can access polyamines released into the circulation by normal cells, wasting cells, gut flora, and dietary sources. A compensatory increase in polyamine transport can explain why drugs targeted exclusively at inhibition of ODC often did not result in the expected levels of polyamine depletion (6, 23, 30), thus complicating experimental interpretation and yielding less than anticipated results in clinical trials (22). However, coadministration of DFMO with a polyamine-free diet (38, 42) or a polyamine transport inhibitor (4) was beneficial in experimental cancer models in vivo and in vitro, respectively. We therefore addressed the effects of NO donors on polyamine transport as well as polyamine biosynthesis. Administration of NO donors does not result in the compensatory increase observed with DFMO, but rather a suppression of polyamine uptake (Fig. 5). At 6 h, only the high concentrations of NO donors demonstrate an effect on polyamine uptake. By 24 h the effects of the NO donors, as well as DFMO, are more apparent (Fig. 5). Thus NO modulation of polyamine transport is a gradual process. The time course for the inhibition of polyamine transporters by antizyme is similar to that for ODC, that is, it occurs rapidly after a short lag phase of <1 h (39, 47). Therefore, the slow onset of polyamine transport suppression by NO occurs in a manner that appears temporally distinct from a directly mediated event, such as nitrosylation, or that described for antizyme. Whether NO indirectly affects antizyme induction has yet to be investigated.
The iNOS-inducing cytokines TNF- and IFN-
also suppressed
polyamine uptake in MCT cells. However, neither
L-NIL (Fig.
6A) nor DAHP, a NOS cofactor
inhibitor (not shown), was able to substantially attenuate these
effects. It should be noted that neither
L-NIL (Fig.
6B) nor DAHP (not shown) was able to
completely inhibit cytokine-stimulated NO generation. Therefore we
cannot unequivocally state that the effects of IFN-
on polyamine
transport are NO independent. However, as shown in Fig.
6B, inhibition of polyamine transport
by TNF-
cannot be attributed to NO generation. Although our data
demonstrate that NO donors suppress polyamine transport (Fig. 5), the
presence of cytokines establishes a complex biological setting where
polyamine transport may be affected by a variety of mediators (for
review, see Refs. 18, 40). Furthermore, the inability of DTT to
effectively reverse cytokine inhibition of ODC activity at 24 h (not
shown) supports a complex and redundant regulation of intracellular
polyamines during inflammation.
These data present NO as the first described endogenous molecule with
the capacity to inhibit both polyamine biosynthesis and transport in a
manner that appears independent of antizyme. Direct inhibition of ODC
by NO, without a compensatory increase in polyamine uptake, could allow
depletion of intracellular polyamine levels required for replication.
NO inhibition of ODC activity could also provide a direct mechanism for
the temporal interregulation of these two arginine pathways during
inflammation, as has been observed in wound healing and experimental
glomerulonephritis (see Fig. 7) (2, 11,
25). The capacity of the cytokines TNF- and IFN-
to suppress
polyamine uptake could effectively contribute to the inhibitory effects
of NO on polyamine biosynthesis in regulating intracellular polyamines.
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ACKNOWLEDGEMENTS |
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We thank E. G. Neilson (mMC), H. Holthofer (ENDO), and F. C. White and M. Kamps (Ras/3T3) for kindly donating cell lines.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants DK-42155, DK-28602, HL-48108, and T32HL-07261, and the Medical Research Service Veterans Affairs Central Office. C. J. Kelly is a Clinical Investigator of Medical Research Service, Veterans Affairs Central Office; M. J. Lortie is a National Kidney Foundation Fellow.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: J. Satriano, UCSD/VAMC, Div. Nephrology-Hypertension, mail code 9111 H, 3350 La Jolla Village Dr., San Diego, CA 92161 (E-mail: jsatriano{at}ucsd.edu).
Received 24 August 1998; accepted in final form 15 January 1999.
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