| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics |
Department of Pathology, Johns Hopkins Medical Institutions [J-N. L., W. F. H., E. S. P.], and Laboratory of Biological Chemistry [M. G.], Research Resources Branch/Flow Cytometry Unit [F. J. C.], and Laboratory of Molecular Genetics [T. S. K., M. K. E.], Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The biological basis for this phenotypic alteration is not clear. However, altered fatty acid metabolism represents a novel target for anti-metabolite therapy because pharmacological inhibition of FAS is selectively cytotoxic for tumor cells, triggering their programmed cell death (11 , 12) . The cytotoxic mechanism of FAS inhibition appears to result from accumulation of the committed substrate, malonyl-CoA, or from related biochemical consequences of the inhibition of an active metabolic pathway, inasmuch as pathway down-regulation before FAS inhibition rescues tumor cell survival (13) . To gain additional insight into the biological role of the fatty acid synthetic pathway for tumor cells and the nature of the growth inhibition resulting from the inhibition of FAS, we have examined the cellular events that follow inhibition of FAS and precede cell death.
Two chemically distinct inhibitors of FAS were studied in parallel to
provide a generic picture of the consequences of the loss of FAS
function. Cerulenin, (2R, 3S)-2,3-epoxy-4-oxo-7,10-trans,
transdodecadienamide, a natural product of
Cephalosporium caerulens, is a specific inhibitor of
FAS enzymes across a broad phylogenetic spectrum
(14, 15, 16)
. Cerulenin irreversibly inhibits FAS by binding
covalently to the active site cysteine of the ß keto acyl synthase
moiety, which performs the condensation reaction between the elongating
fatty acid chain and each successive acetyl or malonyl residue. In
Saccharomyces cerevisiae, a point mutation in FAS that
confers a 30-fold reduction in affinity of the enzyme for cerulenin
also abolishes the growth inhibitory effects of the drug accordingly,
demonstrating that FAS is a critical target for cytotoxic effects of
the drug (17)
. Recently we have synthesized a novel
small-molecule inhibitor of FAS, an 
-methylene-
-butyrolactone
with a C7 hydrocarbon side chain, called c75, with comparable
inhibitory effects on fatty acid synthesis (18)
.
We have recently reported that FAS inhibitors produce rapid, profound blocks of DNA replication and S-phase progression in human cancer cells (19) . Fatty acid synthesis inhibition occurred within 30 min and DNA synthesis inhibition occurred within 90 min of drug exposure, and induction of apoptosis followed several hours later. The suppressive effect of fatty acid synthesis inhibition on DNA replication was indirect, because expression of certain viral oncogenes alleviated it. Here, we report a additional characterization of the cellular response to FAS inhibition. RKO colon carcinoma cells were selected for study because they undergo little apoptosis within the first 24 h after FAS inhibition. Instead, RKO cells exhibit a biphasic stress response marked by early loss of S phase and G2 cyclin-dependent kinase activity and the subsequent accumulation of p53 and p21 proteins, which may protect RKO cells from the cytotoxic effects of FAS inhibition.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
0.2%.
Flow Cytometry and Detection of Apoptosis.
Cells were exposed to cerulenin or c75 for the indicated doses and time
intervals and then detached from plastic with trypsin for flow
cytometry analysis. Apoptosis and DNA content were measured
concurrently by multiparameter flow cytometry using a
FACStarPlus flow cytometer equipped with argon
and krypton lasers (Becton Dickinson). Apoptosis was quantified using
10 µg/ml merocyanine 540 (Sigma), which detects altered plasma
membrane phospholipid packing that occurs early in apoptosis (19
, 22, 23, 24)
. Merocyanine 540-positive cells were identified using
488-nm excitation from an argon laser and a 575-nm DF26 bandpass filter
for collection of events with increased red fluorescence. DNA content
was simultaneously measured from cells stained with 10 µM
Hoechst 33342 (HO33342; Molecular Probes). Cells treated with HO33342
were excited with 350–356-nm light from a krypton laser, and emitted
light was collected using a 467-nm DF22 bandpass filter. Data were
collected and analyzed using CellQuest software (Becton Dickinson).
Determination of the percentages of cells in G1,
S and G2-M was done with Multicycle software
(Phoenix Flow Systems). Figures show representative results of at least
two independently performed experiments.
BrdUrd Detection by Laser Scanning Cytometry.
Dual-parameter detection of BrdUrd labeling and DNA content was
performed using a laser scanning cytometer (Compucyte Corp.). Cell
cultures were pulse-labeled for 20 min with 10 µM BrdUrd
and chased for the indicated times in the absence or presence of drug,
then detached from plastic with trypsin, ethanol-fixed, and applied to
glass slides. Cells were subjected to standard heat-induced epitope
retrieval (DAKO) before staining with anti-BrdUrd antibody (DAKO) and
FITC-conjugated goat antimouse antibody (CALTAG, DAKO Autostainer). DNA
content was assessed after staining with 0.5% propidium iodide. Data
were collected and analyzed using WinCyte software (Compucyte Corp.).
Immunoprecipitation and Immunocomplex-Kinase Assay.
RKO cells (5 x 106/100-mm
plate) were treated with 10 µg/ml cerulenin or c75 for the
indicated time intervals. The control cells received equivalent amounts
of DMSO. After drug treatment, the plates were washed once and lysed
with immunoprecipitation buffer [150 mM Tris (pH
7.4), 150 mM NaCl, 1% Triton X-100, 0.5% NP40, 1
mM ethyleneglyco-bis-tetraacetic acid, 0.2 mM
sodium vanadate, and 0.2 mM phenylmethylsulfonyl
fluoride]. Protein concentration was measured using the BCA Protein
Assay Kit (Pierce). One hundred µg of protein from each sample were
incubated at 4°C for 1 h with 1 µg of primary antibody
(antihuman cyclin A rabbit polyclonal antibody or antihuman cyclin B1
monoclonal antibody; Santa Cruz) and then overnight after the addition
of Protein A or protein G-Sepharose (Santa Cruz). The
immunoprecipitates were washed twice with immunoprecipitation buffer
and once with kinase buffer [10 mM Tris (pH 7.4), 150
mM NaCl, 10 mM MgCl, and 0.5 mM
DTT] and resuspended in 40 µl of kinase buffer containing 1 µg of
histone H1, 25 µM of ATP, and 2.5 µCi of
-32P-ATP. After a 30-min incubation at 30°C,
the reaction was terminated by adding 40 µl of 2x Laemmli sample
buffer. Samples were resolved by electrophoresis through 12%
SDS-polyacrylamide gels and quantitated on a Storm 820 system
(Molecular Dynamics). All samples were run in duplicate, and each
experiment was performed at least twice. Means and standard errors of
one representative experiment are shown in Fig. 3B
.
|
Determination of Fatty Acid Synthesis Pathway Activity.
Cells were plated at 5 x 104
/well
in 1 ml in 24-well plates and incubated overnight. Fatty acid synthesis
was assayed with a 2-h pulse of [U-14C]acetic
acid, 1 µ Ci/well, before Folch extraction and scintillation
counting (6)
. For determination of residual pathway
activity after FAS inhibitor exposure (Fig. 7B)
, a 3-h pulse
of U-[14C]acetic acid, 1 µCi/well, was
performed after 2 h of drug exposure. All determinations were in
triplicate. Data are presented as mean values, with bars showing the
SE. Calculations and graphing were performed in Prism 2.0 (GraphPad).
|
Single Cell Gel Electrophoresis (Comet) Assay.
MCF7 breast cancer cells were treated with cerulenin or c75 for 3 h at doses bracketing 75% survival at 24 h. All experiments were
repeated three times, and duplicate slides from each experiment were
prepared and scored.
The comet assay was performed under alkaline conditions, essentially as described (25) , with some modifications. In brief, cells were suspended in 0.5% low-melting point agarose (LMA; Trevigen) and spread on glass microscope slides precoated with 1% normal agarose. After immersion in lysis solution (Trevigen) at 4°C for a minimum period of 1 h to remove cellular proteins, the slides were immersed in electrophoresis buffer [300 mM NaOH, 1 mM EDTA (pH > 13)] for unwinding DNA, and subjected to electrophoresis (25 V; 300 mA) for 20 min. Neutralized, dehydrated slides were stained with ethidium bromide (2 ng/ml) and comets scored under a Nikon fluorescence microscope (with TRITC filters) coupled to KOMET 4.0 software (Kinetic Imaging, Ltd). The comet parameters, "Olive Tail Moment," "Tail Length" (DNA migration), and "percentage DNA in the tail," were used as indicators of DNA damage. One hundred consecutive cells were scored from the middle of each slide, and the means calculated. The final results were expressed as the (mean of the individual means) ± (SD of the means).
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. When proliferating cells were exposed to 10 µg/ml cerulenin, there
was a redistribution of cells into S phase and
G2-M during the early time points, at 5 and
8 h, compatible with inhibited progression through these cell
cycle phases. Later, at 16 and 24 h, the S-phase fraction
decreased substantially, with a redistribution of cells into
G1 and G2-M. This effect
was characteristic of both cerulenin and c75 treatment on RKO cells, as
well as on other cell lines that had limited apoptotic responses to FAS
inhibitors (not shown).
|
). The progress of BrdUrd pulse-labeled RKO cells through the cell cycle
was monitored over 24 h without inhibition of FAS, or during
exposure to cerulenin (10 µg/ml) or c75 (10 µg/ml). A 20-min
exposure of proliferating cells to BrdUrd labeled the S-phase
population at time 0. Chase samples were collected at 4, 8, 16, and
24 h. In control cultures (Fig. 2A)
, the BrdUrd-labeled
population progressed through G2-M, first
reappearing in the G1 population in the 8-h chase
sample. By 16 h, the BrdUrd-labeled population was in
G1 and S phase again, indicating a complete cell
cycle traverse time of approximately 16 h for RKO cells. By
24 h, labeled and unlabeled populations were distributed
throughout the cell cycle, indicating continued progression and loss of
synchronization (not shown). RKO cells treated with FAS inhibitors
demonstrated substantial delays in cell cycle progression that
corresponded with the flow cytometry single-parameter cell cycle
results (Fig. 1)
. The cerulenin-treated samples are shown in Fig. 2B
; c75-treated populations exhibited a similar response
(not shown). The treated 8-h chase sample showed no BrdUrd-labeled
cells yet reappearing in G1, which was in
agreement with our observation, seen in Fig. 1
, that cells redistribute
into the S and G2-M phases. By 16 h,
most of the BrdUrd-labeled cells had reentered
G1, but very few had entered S phase, and by
24 h most cells, labeled and unlabeled, were in
G1 or G2-M and were still
synchronized, indicating that cell cycle progression had slowed down
substantially.
|
, the kinase activity associated with immunoprecipitated complexes
containing cyclin A decreased to <40% of control levels at 4 and
8 h after exposure to either cerulenin or c75, then increased
moderately at later time points. The kinase activity associated with
immunoprecipitated cyclin B decreased to <5% of control levels by 4
and 8 h after exposure to either cerulenin or c75, then increased
to >80% of control levels at 16 and 24 h. These changes in S and
G2 cdk activity correlated well with the biphasic
pattern of cell cycle distribution demonstrated in Fig. 1
and 2
.
Immunoblots of cyclin A and B levels performed in parallel with the
experiment in Fig. 3
demonstrate that, unlike the associated kinase
activities, the cyclin levels do not decrease until 24 h (not
shown).
FAS Inhibitors Induce p53 and p21 Accumulation, but Not DNA Damage.
The delays in cell cycle progression, with redistribution of cells into
G1 and G2 after FAS
inhibition, were suggestive of cell cycle checkpoint activation by the
tumor suppressor p53, which occurs after genotoxic or other cellular
stresses (28)
. Accumulation of p53 protein, and the
p53-regulated cdk-inhibitor p21WAF1/CIP1, were
assayed by immunoblotting in a parallel time course after inhibition of
FAS (Fig. 4)
. p53 and p21 protein levels were unchanged or decreased during the
early period of FAS-inhibitor exposure. However, treatment with 10
µg/ml of either cerulenin or c75 induced accumulation of p53 and p21
protein at 16 and 24 h in RKO cells (Fig. 4)
. Of note, p21 mRNA
levels did not show increases of the same magnitude, suggesting a
translational and/or posttranslational mechanism(s) regulating p21
accumulation (not shown).
|
. This assay detects DNA strand breaks and a spectrum of alkali-labile
DNA damage at low levels (25
, 29)
. Neither cerulenin nor
c75 induced olive tail moments over background values for untreated
control cells, indicating that DNA damage was not induced by either
agent at doses previously shown to induce inhibition of DNA synthesis
and to reduce clonogenic activity (13
, 19)
. This suggests
that c75 and cerulenin induced cytotoxic, not genotoxic, damage to
cells in an assay that under similar conditions readily detected DNA
damage induced by 5 cGy of irradiation or 25 µM
H2O2. A similar
absence of DNA damage was seen after drug treatment of GM1310B human
lymphoblasts (not shown).
|
. The cell cycle distribution of the non-apoptotic (lower
boxes) and apoptotic (upper boxes) subpopulations of
RKO cells after 24 h of exposure to 5 or 10 µg/ml cerulenin was
determined by multiparameter flow cytometry. Cell cycle position (DNA
content) was determined with HO33342 dye, and apoptosis was detected by
bright staining with merocyanine 540 (MC540), which detects
conformational changes in the plasma membrane that occur early during
apoptosis (22, 23, 24)
. The validity of MC540 staining as a
measure of entry into apoptosis has been confirmed in our experimental
system by evaluation of morphology, change in light scatter parameters,
and TUNEL DNA end-labeling in parallel experiments (Refs.
13
and 19
and data not shown). Entry into
apoptosis after FAS inhibition by cerulenin occurred from
G1, S, and G2-M without
increased sensitivity in any subpopulation. Apoptosis with lack of cell
cycle phase specificity was typical of many experiments with several
cell lines (not shown). The fatty acid synthetic pathway activity in
these paired lines was very similar, so loss of p53 function had no
discernable effect on fatty acid synthesis level (Fig. 7A)
. And the FAS inhibitors produced comparable reduction of
pathway activity in the paired lines (Fig. 7B
; Refs.
13
and 19
). A similar apoptotic response was
seen with three independent RKO-p53 clones and with MCF7-E6, and was
seen after exposure to c75 (Fig. 7, C and E
, and
data not shown). The cytotoxic effects of the FAS inhibitors on these
paired lines were also tested by clonogenic assay (Fig. 7, D and F)
. Comparison of the two cytotoxicity assays shows that
inhibition of FAS causes a reduction in the number of clonable RKO and
MCF7 cells that is not detected by the apoptosis assay. The clonogenic
assay probably detects subpopulations undergoing growth arrest and
potentially other growth-inhibitory processes in addition to those
undergoing rapid apoptosis. However, it appears that the
early apoptosis associated with loss of p53 function illustrated in
Fig. 6
reduces further the clonable fraction, resulting in sensitivity
to FAS inhibitors that is comparable with that seen with other lines
bearing naturally occurring p53 mutations (SW480 colon carcinoma and
SKBr3 breast carcinoma cells).
|
. Cells pretreated with TOFA, and then with cerulenin or c75, showed
similar or greater cell cycle delays than cells exposed only to the FAS
inhibitors. Of note, however, TOFA pretreatment did rescue FAS
inhibitor-mediated apoptosis in RKO-p53 cells, similar to earlier
results (Ref. 13
and not shown), indicating that the
effects of FAS inhibitors on cell cycle progression are distinct from
those mediating apoptotic cell death.
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2
3
4
suggests the rapid onset of a stress response. This
response is characterized by a marked reduction in cyclin A- and
B-associated kinase activities, an early suppression of DNA
replication, and an accumulation of cells in the S and
G2 phases during the first 8 h of drug
exposure, and then by enhanced expression of p53 and p21 proteins, and
growth arrest in G1 and G2
by 16 and 24 h. Although malonyl-CoA accumulation appears involved in triggering apoptosis after FAS inhibition, the growth arrest stress response produced by FAS inhibition may be attributable to altered lipid production, because acetyl-CoA carboxylase inhibition did not relieve it. Most of the fatty acids produced by tumor cells are incorporated into membrane phospholipids, and phospholipid synthesis is inhibited when fatty acid synthesis is inhibited (6 , 7) . Phospholipid biosynthesis is greatest during the G1 and S phases, with doubling of the membrane mass occurring during S phase in preparation for cell division (30) . It is possible, therefore, that limitation of phospholipid synthesis during the S phase affects DNA replication, or independently triggers late cell cycle delays similar to the premitotic checkpoints of yeast (31 , 32) . Notably, two ether lipids that specifically inhibit CTP:phosphocholine cytidylyltransferase, an important enzyme in phospholipid synthesis, produce similar G2-M delays and are selectively cytotoxic to transformed cells (33) . Studies in lower eukaryotes and prokaryotes have shown a requirement for active fatty acid synthesis at the time of cell division, either for simple mitosis or for sporulation (34) . The defects in these systems appear related to chromatin configuration or to the transcriptional activation of key genes. In the FAS inhibition system discussed here, however, the specific mechanisms whereby cyclin A- and B-associated kinase activities decrease in RKO cells remain to be studied in detail.
Role of Tumor Suppressor p53 in the Response to FAS Inhibitors.
The observation that FAS inhibitors induced the accumulation of p53 and
p21 proteins suggested that DNA damage might be occurring, either as a
direct effect of the drugs on the DNA molecule, or as a downstream
effect of FAS inhibition. However, several other observations argue
against DNA damage. First, the toxic effect of cerulenin was found to
be dependent on its ability to inhibit FAS in yeast, thus ruling out a
significant direct effect of cerulenin on DNA (17)
.
Second, toxicity in tumor cells is modulated by alterations in pathway
activity and substrate levels (13
, 19)
. Finally, no DNA
damage was detected using the single cell gel electrophoresis (comet)
screening assay, which has been shown to be very sensitive in detecting
low levels of DNA damage. Consistent with these observations, no
differences were detected in the sensitivity to FAS inhibitors of cells
deficient in ATM (mutated in ataxia telangectasia)
versus controls (not shown).
Whereas the first and most extensively studied function described for the tumor suppressor protein p53 was the induction of growth arrest and apoptosis after DNA damage (20 , 35, 36, 37) , more recently, important roles for p53 have been recognized in the cellular responses to a variety of nongenotoxic metabolic stresses, including hypoxia, acidosis, and perturbations of RNA and protein synthesis (38, 39, 40, 41, 42, 43) . The current study indicates that perturbation of fatty acid synthesis also belongs on the list of metabolic stresses regulated by p53.
The decision between apoptosis and growth arrest after FAS inhibition clearly is influenced by p53 function. Because constitutive fatty acid synthesis activity and inhibitor effects were similar between the paired parental and p53 deficient cells, it is unlikely that levels of malonyl-CoA accumulation were substantially different. The ability of the cell to survive malonyl-CoA accumulation may be greater in cells with intact p53. The relatively low fatty acid synthesis pathway activity of RKO cells (less malonyl-CoA) combined with intact p53 function may underlie the minimal apoptosis produced by FAS inhibitors in RKO cells and in various nontransformed cells.4 It is likely that induction of p21 promotes growth arrest and exerts a protective effect after FAS inhibition, as it has been shown to do in a variety of other stress paradigms (44) . The triggering of apoptosis after FAS inhibition is very rapid, and probably occurs before p21 induction. FAS inhibitors triggered comparable apoptotic responses in the majority of tumor lines with mutant p53 status that we have studied. The predominant pattern of sensitization by loss of p53 function suggests that endogenous fatty acid synthesis will hold special appeal as an experimental therapeutic target. FAS inhibitors combine the target specificity for cancer cells afforded by both elevated fatty acid synthesis and the loss of p53 function.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 This work was supported by NIH Grant
R29CA75219. 
2 To whom requests for reprints should be
addressed, at Department of Pathology, AA154C, Johns Hopkins Bayview
Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224. Phone:
(410) 550-3670; Fax: (410) 550-0075; E-mail: epizer{at}jhmi.edu
3 The abbreviations used are: FAS, fatty acid
synthase; TOFA, 5-(tetradecyloxy)-2-furoic acid; BrdUrd,
bromodeoxyuridine; cdk, cyclin-dependent kinase.
Received 4/28/00. Accepted 12/ 5/00.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
.. Nature (Lond.), 392: 405-408, 1998.[Medline]
This article has been cited by other articles:
|
|
 |
|
  T. Migita, S. Ruiz, A. Fornari, M. Fiorentino, C. Priolo, G. Zadra, F. Inazuka, C. Grisanzio, E. Palescandolo, E. Shin, et al. Fatty Acid Synthase: A Metabolic Enzyme and Candidate Oncogene in Prostate Cancer J Natl Cancer Inst, April 1, 2009; 101(7): 519 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ogino, K. Nosho, J. A. Meyerhardt, G. J. Kirkner, A. T. Chan, T. Kawasaki, E. L. Giovannucci, M. Loda, and C. S. Fuchs Cohort Study of Fatty Acid Synthase Expression and Patient Survival in Colon Cancer J. Clin. Oncol., December 10, 2008; 26(35): 5713 - 5720. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ross, A. M. Najjar, M. Sankaranarayanapillai, W. P. Tong, K. Kaluarachchi, and S. M. Ronen Fatty acid synthase inhibition results in a magnetic resonance-detectable drop in phosphocholine Mol. Cancer Ther., August 1, 2008; 7(8): 2556 - 2565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Xiao, Y. Su, R. C. M. Simmen, and F. A. Simmen Dietary soy protein inhibits DNA damage and cell survival of colon epithelial cells through attenuated expression of fatty acid synthase Am J Physiol Gastrointest Liver Physiol, April 1, 2008; 294(4): G868 - G876. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Beckers, S. Organe, L. Timmermans, K. Scheys, A. Peeters, K. Brusselmans, G. Verhoeven, and J. V. Swinnen Chemical Inhibition of Acetyl-CoA Carboxylase Induces Growth Arrest and Cytotoxicity Selectively in Cancer Cells Cancer Res., September 1, 2007; 67(17): 8180 - 8187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhou, W. F. Han, L. E. Landree, J. N. Thupari, M. L. Pinn, T. Bililign, E. K. Kim, A. Vadlamudi, S. M. Medghalchi, R. El Meskini, et al. Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells Cancer Res., April 1, 2007; 67(7): 2964 - 2971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Browne, E. J. Hindmarsh, and J. W. Smith Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor FASEB J, October 1, 2006; 20(12): 2027 - 2035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. P. Kuhajda Fatty Acid synthase and cancer: new application of an old pathway. Cancer Res., June 15, 2006; 66(12): 5977 - 5980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Chajes, M. Cambot, K. Moreau, G. M. Lenoir, and V. Joulin Acetyl-CoA Carboxylase {alpha} Is Essential to Breast Cancer Cell Survival. Cancer Res., May 15, 2006; 66(10): 5287 - 5294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Carlisle-Moore, C. R. Gordon, C. A. Machutta, W. T. Miller, and P. J. Tonge Substrate Recognition by the Human Fatty-acid Synthase J. Biol. Chem., December 30, 2005; 280(52): 42612 - 42618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Brusselmans, E. De Schrijver, G. Verhoeven, and J. V. Swinnen RNA Interference-Mediated Silencing of the Acetyl-CoA-Carboxylase-{alpha} Gene Induces Growth Inhibition and Apoptosis of Prostate Cancer Cells Cancer Res., August 1, 2005; 65(15): 6719 - 6725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Menendez, L. Vellon, and R. Lupu Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene Ann. Onc., August 1, 2005; 16(8): 1253 - 1267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Knowles, F. Axelrod, C. D. Browne, and J. W. Smith A Fatty Acid Synthase Blockade Induces Tumor Cell-cycle Arrest by Down-regulating Skp2 J. Biol. Chem., July 16, 2004; 279(29): 30540 - 30545. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Vecchini, V. Ceccarelli, F. Susta, P. Caligiana, P. Orvietani, L. Binaglia, G. Nocentini, C. Riccardi, G. Calviello, P. Palozza, et al. Dietary {alpha}-linolenic acid reduces COX-2 expression and induces apoptosis of hepatoma cells J. Lipid Res., February 1, 2004; 45(2): 308 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhou, P. J. Simpson, J. M. McFadden, C. A. Townsend, S. M. Medghalchi, A. Vadlamudi, M. L. Pinn, G. V. Ronnett, and F. P. Kuhajda Fatty Acid Synthase Inhibition Triggers Apoptosis during S Phase in Human Cancer Cells Cancer Res., November 1, 2003; 63(21): 7330 - 7337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rossi, E. Graner, P. Febbo, L. Weinstein, N. Bhattacharya, T. Onody, G. Bubley, S. Balk, and M. Loda Fatty Acid Synthase Expression Defines Distinct Molecular Signatures in Prostate Cancer Mol. Cancer Res., August 1, 2003; 1(10): 707 - 715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. De Schrijver, K. Brusselmans, W. Heyns, G. Verhoeven, and J. V. Swinnen RNA Interference-mediated Silencing of the Fatty Acid Synthase Gene Attenuates Growth and Induces Morphological Changes and Apoptosis of LNCaP Prostate Cancer Cells Cancer Res., July 1, 2003; 63(13): 3799 - 3804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. D. Camassei, R. Cozza, A. Acquaviva, A. Jenkner, L. Rava, R. Gareri, A. Donfrancesco, C. Bosman, P. Vadala, T. Hadjistilianou, et al. Expression of the Lipogenic Enzyme Fatty Acid Synthase (FAS) in Retinoblastoma and Its Correlation with Tumor Aggressiveness Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2399 - 2403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Kumar-Sinha, K. W. Ignatoski, M. E. Lippman, S. P. Ethier, and A. M. Chinnaiyan Transcriptome Analysis of HER2 Reveals a Molecular Connection to Fatty Acid Synthesis Cancer Res., January 1, 2003; 63(1): 132 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Van de Sande, E. De Schrijver, W. Heyns, G. Verhoeven, and J. V. Swinnen Role of the Phosphatidylinositol 3'-Kinase/PTEN/Akt Kinase Pathway in the Overexpression of Fatty Acid Synthase in LNCaP Prostate Cancer Cells Cancer Res., February 1, 2002; 62(3): 642 - 646. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
