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Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224 [E. S. P., J. T., W. F. H., M. L. P., F. P. K.]; Research Resources Branch/Flow Cytometry Unit, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224 [F. J. C.]; and Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218 [G. L. F., C. A. T.]
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Introduction |
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Fig. 1A
outlines the portion of the FA synthesis pathway containing
the target enzymes of the inhibitors used in this study. TOFA is an
allosteric inhibitor of ACC, blocking the carboxylation of acetyl-CoA
to malonyl-CoA. Once esterified to CoA, TOFA-CoA allosterically
inhibits ACC with a mechanism similar to long chain acyl-CoAs, the
physiological end-product inhibitors of ACC (10)
. Both
cerulenin (11)
and C75 (8)
are inhibitors of
FAS, preventing the condensation of malonyl-CoA and acetyl-CoA into
FAs. Cerulenin is a suicide inhibitor, forming a covalent adduct with
FAS (12)
, whereas C75 is likely a slow-binding inhibitor
(13)
. We now report that using TOFA, we achieved FA
synthesis inhibition in human breast cancer cell lines comparable to
inhibition by cerulenin or C75. Surprisingly, however, TOFA was
essentially nontoxic to human breast cancer cells. These data suggest
that FA starvation is not a major source of cytotoxicity to cancer
cells in serum supplemented culture. Rather, high levels of the
substrate, malonyl-CoA, resulting specifically from inhibition of FAS,
may mediate cytotoxicity of cerulenin and C75.
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Materials and Methods |
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Cell Lines, Culture Conditions, Metabolic Labeling, and
Clonogenic Assays.
The human breast cancer cell lines, SKBR3 and MCF7 were maintained in
RPMI with 10% fetal bovine serum. Cells were screened periodically for
Mycoplasma contamination (Gen-probe). All inhibitors were
added as stock 5 mg/ml solutions in DMSO. For FA synthesis activity
determinations, 5 x 104
cells/well in 24-well plates were pulse labeled with
[U14C]acetate after exposure to drug, and
lipids were extracted and quantified as described previously
(8)
. For MCF7 cells, pathway activity was determined after
2 h of inhibitor exposure. SKBR3 cells demonstrated slower
response to FAS inhibitors, possibly because of their extremely high
FAS content, so pathway activity was determined after 6 h of
inhibitor exposure. For clonogenic assays, 4 x 105 cells were plated in
25-cm2 flasks with inhibitors added for 6 h
in concentrations listed. To rescue MCF7 cells with TOFA (see Fig. 3C
), the TOFA was added 1 h prior to the FAS
inhibitors. Equal numbers of treated cells and controls were plated in
60-mm dishes. Clones were stained and counted after 7–10 days.
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Measurement of Malonyl-CoA.
Malonyl-CoA levels were measured in MCF-7 cells using the HPLC method
of Corkey (16)
. Briefly, 2.5 x 105 cells/well in 24-well plates were subjected
to 1.2 ml of 10% trichloroacetic acid at 4°C after various
drug treatments. The pellet mass was recorded, and the supernatant was
washed six times with 1.2 ml of ether and reduced to dryness using
vacuum centrifugation at 25°C. CoA esters were separated and
quantitated using reversed-phase HPLC on a 5-µm Supelco C18
column with a Waters HPLC system running
Millenium32 software, monitoring 254 nm as
the maximum absorbance for CoA. The following gradients and buffers
were used: buffer A, 0.1 M potassium phosphate, pH 5.0;
buffer B, 0.1 M potassium phosphate, pH 5.0, with 40%
acetonitrile. Following a 20-min isocratic run with 92% buffer A, 8%
buffer B at 0.4 ml/min, flow was increased to 0.8 ml/min over 1 min,
whereupon a linear gradient to 10% buffer B was run until 24 min and
then held at 10% buffer B until 50 min, at which point a linear
gradient was run to 100% buffer B at 55 min, completing at 60 min. The
following CoA esters (Sigma) were run as standards: malonyl-CoA,
acetyl-CoA, glutathione-CoA, succinyl-CoA, HMG-CoA, and free CoA.
Samples and standards were dissolved in 50 µl of buffer A. CoA esters
eluted sequentially as follows: malonyl-CoA, glutathione-CoA, free CoA,
succinyl-CoA, HMG-CoA, and acetyl-CoA. Quantitation of CoA esters was
performed by the Millenium32 software.
Xenograft Studies.
s.c. flank xenografts of the human breast cancer cell line, MCF-7
in nu/nu female mice (Harlan) were used to study the antitumor
effects of C75 in vivo. All animal experiments complied with
institutional animal care guidelines. All mice received a 90-day
slow-release s.c. estrogen pellet (Innovative Research) in the anterior
flank 7 days before tumor inoculation. MCF7 cells
(107 cells) were xenografted from culture in DMEM
supplemented with 10% FBS and 10 µg/ml insulin. Treatment began when
measurable tumors developed about 10 days after inoculation. Eleven
mice (divided between two separate experiments of five and six mice)
were treated i.p. with weekly doses of C75 at 30 mg/kg in 0.1 ml of
RPMI. Dosing was based on a single dose LD10
determination of 40 mg/kg in BALB/c mice; 30 mg/kg has been well
tolerated in outbred nude mice. Eleven control mice (divided in the
same way as the treatment groups) received RPMI alone. Tumor volume was
measured with calipers in three dimensions. Experiment was terminated
when controls reached the surrogate end point. In a parallel experiment
to determine FA synthesis activity in treated and control tumors, a
group of MCF-7 xenografted mice were treated with C75 or vehicle at
above doses and sacrificed after 3 h. Tumor and liver tissue were
ex vivo labeled with [U14C], lipids
were extracted and counted as described (3)
. In an
additional parallel experiment to histologically examine treated and
control tumors, six C75-treated and six vehicle control mice were
sacrificed 6 h after treatment. Tumor and normal tissues were
fixed in neutral-buffered formalin and processed for routine histology,
and immunohistochemistry for FAS was performed.
FAS Immunohistochemistry.
Immunohistochemistry for FAS was performed on the MCF-7 xenografts
using a mouse monoclonal anti-FAS antibody (1)
at 1:2000
on the DAKO Immunostainer using the LSAB2 detection kit.
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Results and Discussion |
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). The
maximal pathway inhibition achieved with each drug was somewhat
variable among cell lines. In numerous similar experiments (not shown),
TOFA maximally inhibited FA synthesis in the 1–5 µg/ml dose range in
all cell lines tested, and cerulenin and C75 maximally inhibited FA
synthesis at about 10 µg/ml Although all inhibitors reduced FA
synthesis to comparable degrees, TOFA was nontoxic or stimulatory to
the cancer cell growth in the dose range for ACC inhibition, as
measured by clonogenic assays, whereas cerulenin and C75 were
significantly cytotoxic in the dose range for FAS inhibition (Fig. 1, C and E
). The profound difference between the
cytotoxic effects of ACC and FAS inhibition demonstrated that the acute
reduction of FA production per se was not the major source
of cell injury after FAS inhibition. Alternatively, these data
suggested that cytotoxicity resulted from a biochemical effect of FAS
inhibition that was not shared by ACC inhibition.
Malonyl-CoA Levels Were Markedly Increased with FAS Inhibition and
Reduced by TOFA.
The most obvious difference in the expected results of inhibiting these
two enzymes was that malonyl-CoA levels should fall after ACC
inhibition but increase after FAS inhibition. Although not previously
investigated in eukaryotes, recent data in Escherichia coli
have demonstrated elevated levels of malonyl-CoA resulting from
exposure to cerulenin (17)
.
Direct measurement of CoA derivatives in MCF-7 cells by reversed-phase
HPLC of acid soluble extracts from drug-treated cells confirmed that
both cerulenin and C75 caused a rapid increase in malonyl-CoA levels,
whereas TOFA reduced malonyl-CoA levels. Fig. 2A
is a representative chromatograph demonstrating the
separation and identification of CoA derivatives important in cellular
metabolism. Malonyl-CoA is the first of these to elute, with a column
retention time of 19–22 min. The overlay of chromatographs in Fig. 2B
shows that cerulenin treatment led to a marked increase
in malonyl-CoA over the control, whereas TOFA caused a significant
reduction. The chemical identity of the malonyl-CoA was independently
confirmed by spiking samples with standards (not shown). The analysis
of multiple experiments shown in Fig. 2C
demonstrated that
following a 1-h exposure to cerulenin or C75 at 10 µg/ml, malonyl-CoA
levels increased by 930 and 370%, respectively, over controls, whereas
TOFA treatment (20 µg/ml) led to a 60% reduction of malonyl-CoA
levels. The concentration of TOFA required for maximal reduction of
malonyl-CoA levels was 4-fold higher than the dose for pathway
inhibition shown in Fig. 1, B and D
. However,
optimal cultures for extraction of CoA derivatives had 5-fold higher
cell density than the cultures used in the other biochemical and
viability assays presented. The remarkable increase in malonyl-CoA
after FAS inhibition can be attributed in part to the release of
long-chain fatty acyl-CoA inhibition of ACC, leading to an increase in
ACC activity (Fig. 1A
). Moreover, the cerulenin-induced
increase in malonyl-CoA levels occurred within 30 min of treatment
(930 ± 15% increase over control, data not shown),
within the time frame of FA synthesis inhibition and well before the
onset of DNA synthesis inhibition or early apoptotic events
(8)
. Thus, high levels of malonyl-CoA were a
characteristic effect of FAS inhibitors and temporally preceded the
other cellular responses, including apoptosis.
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) abrogated the cytotoxic effect of cerulenin alone in
clonogenic assays. In MCF7 cells (Fig. 3C
), TOFA rescued
both cerulenin and C75 when cells were exposed to TOFA for 1 h
prior to the FAS inhibitors. Representative flow cytometric analyses of
SKBR3 cells (Fig. 3B
) and MCF7 (Fig. 3D
)
substantiated these findings, because TOFA rescued cells from cerulenin
induced apoptosis. These experiments also confirmed the differential
cytotoxicity between TOFA (<5% increase in apoptosis; no reduction in
clonogenicity) compared to cerulenin (>85% apoptosis; 70% reduction
in clonogenicity). Taken together, these studies suggest that high
malonyl-CoA levels may play a role in the cytotoxic effect of FAS
inhibitors on cancer cells.
In Vivo Inhibition of FAS Led to Reduced Tumor Growth.
Previous studies have demonstrated local efficacy of cerulenin against
a human cancer xenograft (18)
but were limited by the
failure of cerulenin to act systemically. The similar responses of
breast cancer cells to cerulenin and C75 in vitro suggested
that C75 might be effective in vivo against xenografted
breast cancer cells. To determine whether the effects of FAS inhibition
seen in vitro would translate to an in vivo
setting requiring systemic activity, we tested C75 against s.c. MCF-7
xenografts in athymic nude mice, to quantitate effects on FA synthesis
and the growth of established solid tumor.
FA synthesis pathway activity in tissues of xenografted mice was
determined by ex vivo pulse labeling with
[U14C]acetate. The tumor xenografts had 10-fold
higher FA synthesis activity than liver, highlighting the difference in
pathway activity between benign and malignant tissues (Fig. 4A
). FAS expression in the MCF-7 xenograft paralleled the high
level of FA synthesis activity (Fig. 4B
). i.p. injections of
C75 at 30 mg/kg reduced FA synthesis in ex vivo labeled
liver by 76% and in the MCF-7 xenografts by 70% within 3 h (Fig. 4A
). These changes in FA synthesis preceded histological
evidence of cytotoxicity in the xenograft, which became evident 6 h after treatment (Fig. 4, C and D
). The
C75-treated xenografts showed numerous apoptotic bodies throughout the
tumor tissue, which were not seen in vehicle-treated tumors.
Histological analysis of liver and other host tissues following C75
treatment showed no evidence of any short or long term toxicity (not
shown).
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). After 32 days of weekly
treatments, there was a greater than 8-fold difference in tumor growth
in the treatment group compared to vehicle controls. Similar to
cerulenin, transient reversible weight loss was the only toxicity noted
(18)
. The systemic pharmacological activity of C75 provided the first analysis of the outcome of systemic FAS inhibitor treatment. The significant antitumor effect of C75 on a human breast cancer xenograft in the setting of physiological levels of ambient FAs was similar to the in vitro result in serum supplemented culture and was consistent with a cytotoxic mechanism independent of FA starvation. Furthermore, the result suggested that malonyl-CoA accumulation may not be a significant problem in normal tissues, possibly because FA synthesis pathway activity is normally low, even in lipogenic organs, such as the liver. It is of further interest that whereas malonyl-CoA was the predominant low molecular weight CoA conjugate detected in breast cancer cells in these experiments, other studies have reported predominantly succinyl-CoA and acetyl-CoA in cultured hepatocytes (16) . Differences in CoA derivative profiles may be indicative of larger differences in energy metabolism between cancer cells and hepatocytes.
The identification of malonyl-CoA as a potential mediator of cytotoxicity, possibly via induction of apoptosis in cancer cells, although unanticipated, was not surprising given its pivotal role in cellular metabolism. In addition to its function as a substrate for FA synthesis, malonyl-CoA regulates FA oxidation by inhibiting carnitine palmitoyltransferase I at the outer mitochondrial membrane (19) . Physiologically, the elevated levels of malonyl-CoA occurring during FA synthesis reduce FA oxidation to prevent a futile cycle of simultaneous FA synthesis and degradation. During starvation or feeding with high-fat diets, fat synthesis ceases, malonyl-CoA levels fall, and FAs enter the mitochondrion for energy production. Malonyl-CoA is thus a crucial regulatory metabolic intermediate in cellular energy metabolism. How superphysiological levels of malonyl-CoA may lead to apoptosis is not yet known; however, carnitine palmitoyltransferase I, which is regulated by malonyl-CoA, has been shown to interact directly with Bcl-2 at the mitochondrial membrane (20) . This convergence suggests that high levels of malonyl-CoA may either induce apoptosis directly or alter mitochondrial metabolism to increase susceptibility to apoptosis from other signals. Thus, further investigation of malonyl-CoA and CoA metabolism in cancer cells may yield new insights into cancer cell metabolism and selective susceptibility to antimetabolite therapy.
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FOOTNOTES |
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1 Supported in part by grants from the Department
of the Army, NIH, American Chemical Society, and the Raynam Research
Fund, by a Cope Scholar Award, and the Stewart Trust. 
2 To whom requests for reprints should be
addressed, at Department of Pathology, The Johns Hopkins University
School of Medicine, 4940 Eastern Avenue, Baltimore, Maryland 21224.
Phone: (410) 550-3670; Fax: (410) 550-0075.
3 The abbreviations used are: FAS, fatty-acid
synthase; ACC, acetyl-CoA carboxylase; FA, fatty acid; HPLC,
high-performance liquid chromatography; TOFA,
5-(tetradecyloxy)-2-furoic acid; s.c., subcutaneous; i.p.,
intraperitoneal.
Received 8/ 2/99. Accepted 11/23/99.
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E. W. Gabrielson, M. L. Pinn, J. R. Testa, and F. P. Kuhajda Increased Fatty Acid Synthase is a Therapeutic Target in Mesothelioma Clin. Cancer Res., January 1, 2001; 7(1): 153 - 157. [Abstract] [Full Text]
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S. W. Ki, K. Ishigami, T. Kitahara, K. Kasahara, M. Yoshida, and S. Horinouchi Radicicol Binds and Inhibits Mammalian ATP Citrate Lyase J. Biol. Chem., December 8, 2000; 275(50): 39231 - 39236. [Abstract] [Full Text] [PDF]
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F. P. Kuhajda, E. S. Pizer, J. N. Li, N. S. Mani, G. L. Frehywot, and C. A. Townsend Synthesis and antitumor activity of an inhibitor of fatty acid synthase PNAS, March 28, 2000; 97(7): 3450 - 3454. [Abstract] [Full Text] [PDF]
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