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Molecular Nutrition Unit, Centre de Recherche du Centre Hospitalier de l’Université de Montréal and Institut du Cancer de Montréal [S. H., Y. L., M. P.], and Departments of Microbiology and Immunology [Y. L.] and Nutrition and Biochemistry [M. P.], Université de Montréal, Montréal, Québec, H2L 4M1 Canada
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ABSTRACT |
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INTRODUCTION |
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The question of why epidemiological studies have not been as consistent as animal studies in relating fat intake and breast cancer risk is a complex one. On one hand, nutritional epidemiology suffers from profound imprecision of exposure measurements. It has been argued that this imprecision leads to substantial underestimation of disease-exposure associations, such as relative risk and dose response. Also, all cohort studies focused on fat consumption during adulthood, whereas it is possible that fat intake during adolescence may be of greater importance for subsequent breast cancer development. On the other hand, inconsistencies also exist in experimental studies. A recent meta-analysis of about 100 rodent studies indicated that n-6 polyunsaturated fatty acids have a strong tumor-enhancing effect, whereas saturated fatty acids have a weaker effect (7) . Monounsaturated fatty acids and n-3 polyunsaturated fatty acids have no statistically significant effects (7) . However, as reviewed by Hardy et al. (8) , many studies reported contradictory conclusions with respect to the respective actions of the different types of fatty acids, particularly for oleic acid, in the animal mammary tumor models. Because the ratio, type, and amount of fatty acids may influence tumor development in different ways in animals, conflicting results may be explained in part by the fact that fat is generally administered as a mixture of several different fatty acids and not as individual fatty acids (8 , 9) . Different effects of saturated and unsaturated fatty acids on cell proliferation and promotion have also been documented in breast cancer cell culture studies (10, 11, 12, 13, 14) . These inconsistencies could be related to differences in culture conditions or to the use or nonuse of albumin-bound fatty acids (15 , 16) . Thus, several in vitro studies tested the action of fatty acids unbound to BSA at concentrations far above their critical micellar concentrations. This raises doubts about the results obtained with such nonphysiological conditions.
In an effort to clarify these problems, we based our works on the
premise that assessing the effects of individual major dietary fatty
acids on cell proliferation will help us to understand the mechanisms
by which fatty acids may influence tumor cells and therefore be helpful
in the design of future epidemiological studies and, eventually,
dietary counseling. Relatively little information exists on the
biochemical pathways by which fatty acids influence tumor cell
proliferation. The discovery that
FAS,3
an enzyme essential to fatty acid metabolism, is a prognostic indicator
of breast cancer progression strengthens the hypothesis that fatty
acids are involved in the regulation of tumor cell growth
(17, 18, 19, 20)
. Also, consistent with this view is the
observation that troglitazone, a ligand for peroxisome
proliferator-activated receptor 
, a nuclear receptor that also binds
various fatty acids, markedly influences the growth and apoptosis of
various cancer cells (21, 22, 23, 24, 25)
. We recently proposed that
fatty acids could influence insulinoma cell growth through the
induction of proto-oncogenes like c-fos via
Ca2+ and protein kinase C signaling
(26)
. Thus, much remains to be learned about the primary
target of fatty acids in relation to oncogenesis. PI3-K phosphorylates
inositol lipids that act as second messengers for several pathways
related to cell proliferation and apoptosis (27, 28, 29, 30)
.
Whether long-chain fatty acids influence cell proliferation via PI3-K
is unknown.
In the present study, the actions of the two most abundant circulating fatty acids, oleate and palmitate, were investigated in established human breast cancer cell lines after a short period of serum starvation. We found that oleate (C:18:1; unsaturated fatty acid) stimulates cell proliferation, whereas palmitate (C:16; saturated fatty acid) promotes apoptosis. Moreover, oleate protects cells against palmitate-induced apoptosis. Evidence that PI3-K may be implicated in the mode of action of these fatty acids is also provided.
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MATERIALS AND METHODS |
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99% purity; Sigma) at 37°C with 5% fraction V
essentially fatty acid-free BSA (Sigma) as described previously
(26)
. After being adjusted to pH 7.4, the solution was
filtered through a 0.22 µm filter, and the fatty acid concentration
was measured using a NEFAC kit (Wako Chemicals GmbH). When
BSA-bound fatty acids were added to serum-free culture medium, the
final concentration of BSA was always adjusted to 0.5%.
[3
H]Thymidine Incorporation.
Cells were seeded at 5000 cells/well in 96-well plates and incubated
for 24 h in standard medium. After a 24-h starvation period in
media without insulin and serum but with 0.5% fatty acid-free BSA,
cells were incubated without or with BSA-bound fatty acids for 24 h. DNA synthesis was then assayed with a pulse of
[3
H]thymidine (1 µCi/well; specific activity,
71 Ci/mmol) during the last 4 h of incubation. Cells were
harvested with a PHD cell harvester from Cambridge Technology
(Watertown, MA), and the radioactivity retained on the dried glass
fiber filters was counted using a Packard scintillation
spectrophotometer (31)
.
Apoptosis Assay.
Cells were seeded in 100-mm Petri dishes at 1 x 106 cells/dish and treated as described in the
figure legends. To determine the percentage of apoptotic cells, the
detached cells present in the culture medium and in a 5-ml PBS wash of
the dish were centrifuged at 1000 x g for 5
min, resuspended in PBS, and counted with a hemocytometer. The attached
cells were trypsinized and counted. The percentage of apoptotic cells
in triplicate dishes was evaluated by dividing the number of detached
cells by the total number of cells (detached cells + attached
cells). This method for quantification of apoptotic cells gave results
that were similar within 5% to a direct counting of cells with
apoptotic morphology (cell rounding and blebbing) in randomly selected
fields using a Nikon Diaphot inverted photomicroscope (x200).
Analysis of DNA Laddering by Agarose Gel Electrophoresis.
Cellular DNA was extracted from detached cells by the salting out
procedure described by Miller et al. (32)
.
Electrophoresis was done in 1.5% agarose gels in Tris-borate buffer
(pH 8.0). DNA was visualized under UV illumination after staining with
ethidium bromide.
Protein Extraction and Analysis.
Total protein extracts were prepared by lysing cells in protein
extraction buffer [65 mM Tris (pH 6.8), 6 M
urea, and 2% SDS] followed by sonication to shear the DNA. After
determination of protein concentration using the Bio-Rad DC (detergent
compatible) colorimetric assay with BSA as a standard, DTT was added to
a concentration of 5% (v/v), and the samples were boiled for 5 min
before performing SDS-PAGE and Western blotting. After incubation with
PARP/Ab-2, a mouse monoclonal antibody (Calbiochem) directed against
PARP, the membrane was incubated with horseradish peroxidase-conjugated
goat antimouse antibody (Amersham Corp.), and the bound peroxidase was
revealed using the SuperSignal (Pierce) detection kit.
PI3-K Activity Measurements.
MDA-MB-231 cells were grown in 150-mm Petri dishes. After a 5-min
incubation period in the presence of various test substances, PI3-K was
assayed as described previously (33)
. In brief, PI3-K was
immunoprecipitated from 5 mg of total protein extracts with an
anti-p85PI3-K antibody (Santa Cruz Biotechnology, Santa Cruz, CA) and
resuspended in 50 µl of a buffer containing 20 mM
Tris-HCl (pH 7.5), 100 mM NaCl, and 100 mM
EGTA. After incubation for 10 min with 10 µg of
L-
-phosphatidylinositol, 10 µCi of
[32P]ATP were added with 10 mM
MgCl2. The reaction was stopped after 4 min at
room temperature with a mixture of
CHCl3-methanol-HCl (100:200:2), and the lipids
were extracted and separated by TLC on silica gel plates. PI3-K
activity was quantified through phosphatidylinositol 3-phospate
formation.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. In contrast, palmitate had a drastically different effect
because it decreased the [3
H]thymidine
incorporation in the four cell lines by 30–90% (Fig. 1B)
.
The T-47-D cells, which were insensitive to oleate, exhibited
sensitivity to palmitate to an extent similar to that of MCF-7 and
ZR-75-1 cells. Interestingly, the opposite effects of both fatty acids
were most pronounced in hormone-independent MDA-MB-231 cells. The
results indicate that whereas DNA replication was stimulated by oleate
in the majority of the tested breast cancer cells, it was inhibited by
palmitate in all of them.
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, the effects of oleate and palmitate on
[3
H]thymidine incorporation were dose
dependent. The stimulation of DNA synthesis by oleate, which was
detectable at a concentration of 1 µM, reached a plateau
at 10 µM that was sustained up to 400 µM,
the highest tested concentration (Fig. 2A)
. The cell
proliferation-inhibitory effects of palmitate occurred in the 10–100
µM range. The microscopic observation of
palmitate-treated cells revealed that this fatty acid caused a
dose-dependent rise in the percentage of cells exhibiting morphological
signs of apoptosis (cell blebbing, rounding, and detachment) that
paralleled the decreased [3
H]thymidine
incorporation (Fig. 2B)
. Similar results were obtained with
oleate and palmitate purchased from two other companies (data not
shown). It should be noted that on the basis of recent estimates of the
free concentrations of fatty acids in the blood (35)
and
at different albumin:fatty acid ratios (36)
, the free
concentrations of both palmitate and oleate in the cell culture medium
should be in the nanomolar range.
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. The growth of control cells stopped after 1 day of culture, and at 3
days after serum starvation, the number of attached cells had dropped
considerably. Microscopic observations revealed that most cells that
detached from the dishes exhibited apoptotic morphological changes
(data not shown). In sharp contrast, the number of oleate-treated cells
increased 2-fold during the same 3-day period and remained constant
over the next 2 days. However, the growth of these cells was less rapid
than that of serum-treated cells, and a plateau was attained at a much
lower density. Although the majority of oleate-treated cells did not
exhibit morphological signs of apoptosis, they differed somewhat from
serum-treated cells by exhibiting a higher content of dark inclusions
in their cytoplasm (Fig. 4A)
. Taken together, the data indicate that the death process
induced in MDA-MB-231 cells by serum starvation is counteracted by
oleate. Conversely, palmitate considerably promotes the death of
serum-starved cells.
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, a small amount
of the Mr 89,000 PARP
degradation product was detected (Fig. 4B)
. Oleate almost
completely prevented PARP cleavage, whereas palmitate increased it.
When DNA degradation was analyzed on the entire cell populations,
typical DNA laddering was barely visible (data not shown). However,
when the DNA was extracted only from cells floating in the medium,
laddering that was faintly visible in the control situation was
apparent in the palmitate condition. Oleate nearly completely prevented
DNA degradation (Fig. 4C)
. These results establish that
oleate exerts an antiapoptotic effect on serum-starved MDA-MB-231
cells, whereas palmitate is proapoptotic.
To determine whether oleate may protect cells against death triggered
by palmitate, the level of apoptosis induced by palmitate (100
µM) in the presence of an increasing concentration of
oleate was evaluated (Fig. 5)
. Fifty % protection was already attained at the lowest tested
concentration of oleate (1 µM). At 10 µM,
the percentage of apoptosis was similar to that of controls (9%).
Thus, a 1:10 molar ratio of oleate versus palmitate was
sufficient for full protection. The cells protected by oleate against
palmitate had a morphological appearance similar to that of cells
treated with oleate alone (Fig. 4A)
. Moreover, cells
incubated in presence of palmitate (100 µM)
plus oleate (30 µM) exhibited as little PARP
cleavage and DNA fragmentation as control cells (Fig. 4, B and C)
. The proapoptotic action of palmitate was also
observed in the estrogen-dependent cell line T-47-D. As shown in Fig. 4D
, palmitate induced qualitatively similar changes in PARP
cleavage in T-47-D cells and in the estrogen-independent cell line
MDA-MB-231, and PARP cleavage could be counteracted by oleate. The
morphological changes caused by both fatty acids, alone or in
combination, were also similar in both cell lines (data not shown).
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. Because PI3-K inhibitors had only a weak effect (
20% decrease) on
the proliferation of control cells (data not shown), these results
suggested that PI3-K plays an important role in the proliferative
effect of oleate. To confirm that PI3-K is involved in the action of
oleate, PI3-K activity was measured in extracts of cells incubated for
5 min with the fatty acid (Fig. 7)
. In each of six separate experiments, oleate stimulated PI3-K activity
by a factor that averages to 2-fold. For comparison, 5% FBS also
activated PI3-K by 2-fold (n = 2; data not
shown). In contrast, palmitate caused a 60% reduction of PI3-K
activity, whereas the mixture of the two fatty acids had no effect.
These results provide supporting evidence that PI3-K is implicated in
the mode of action of oleate and palmitate on breast cancer cell
proliferation and apoptosis, respectively.
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DISCUSSION |
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Stimulation of MDA-MB-231 cell proliferation by oleate has also been observed by others in the presence of 5% FBS (37) or in serum-free medium (15) . Provided that these observations may be extended to the in vivo situation, it can be postulated that a diet rich in oleate may favor mammary tumor progression. Thus, obesity is characterized by elevated circulating FFAs, as well as insulin resistance (38) and an increase in the risk of breast (39) and colorectal cancer (40) . Furthermore, a positive correlation exists between these pathological diseases (40, 41, 42, 43) .
In contrast, palmitate decreased the proliferation of MDA-MB-231 cells. Other groups have also observed that saturated fatty acids diminish the proliferation rate of human breast cancer cells (14 , 15) ; however, to our knowledge, this is the first time it has been shown to be associated with the induction of apoptosis. Palmitate also induces apoptosis in isolated pancreatic islets (44) , hematopoietic precursor cell line LyD9 (45) , and neonatal rat cardiomyocytes (46) . The mechanism of the proapoptotic action of palmitate is uncertain. Palmitate is a precursor of ceramide, whereas oleate is not (47) . Evidence has been provided that palmitate might induce apoptosis via ceramide production in isolated pancreatic islets (44) and in the hematopoietic precursor cell line LyD9 (45) . Whether de novo synthesis of ceramide is causally linked to the proapoptotic action of palmitate in MDA-MB-231 cells remains to be evaluated. Another possibility is the inhibition of FAS, the enzyme responsible for the endogenous synthesis of fatty acids. Thus, palmitate inhibits FAS activity and gene expression in various cell types (48) , and the inhibition of this enzyme by cerulenin has been reported to induce apoptosis in breast cancer cells (17) .
The effect of palmitate on MDA-MB-231 apoptotic cell death is reversed by oleate. Moreover, the combination of the two fatty acids at 100 µM resulted in an increased proliferation of MDA-MB-231 cells (data not shown). An antiapoptotic action of oleate against palmitate has also been observed in neonatal rat cardiomyocytes in which equimolar amounts of both fatty acids were necessary for full protection (46) . The opposite action of different fatty acids on breast cancer cell growth may explain why the results of epidemiological and animal studies using different diets are often conflicting. In vivo animal studies always used oils that were rich in particular fatty acids but also contained other fatty acids that may have influenced tumor promotion in a markedly different manner.
PI3-K activation after growth factor stimulation is closely associated with increased proliferation and survival (27 , 28) . Oleate appears to act like a growth factor because it stimulates cell proliferation at a very low concentration and activates PI3-K in MDA-MB-231 cells. In contrast, palmitate reduced basal PI3-K activity in this cell line. To our knowledge, this provides the first evidence of changes in PI3-K activity by various fatty acids for any cell type. The very rapid response to treatment renders an effect involving changes in protein synthesis unlikely. It rather suggests signaling via membrane receptors such as receptor tyrosine kinases or G protein-coupled receptors, which are known to act via PI3-K activation (49 , 50) . Interestingly, it has recently been shown that oleate, but not palmitate, can activate the epithelial growth factor receptor in endothelial cells (51) . PI3-K activation could also occur via CD36, a cell surface protein that can interact with fatty acids (52) and activate members of the src protein tyrosine kinase family (53) .
Taken together our results support the view that the type of fatty acids (saturated, monounsaturated, and polyunsaturated) and their ratios in the diet in addition to the total amount of fat influence mammary carcinogenesis. It will be of interest to determine the detailed mechanisms of palmitate and oleate action on breast cancer cell growth, particularly upstream and downstream of PI3-K. Because the activity of PI3-K, a key signal transduction protein implicated in cell growth control, is modulated by exogenous fatty acids (the present study) and glucose (31) , the possibility should be considered that PI3-K provides a link between excessive calorigenic nutrient intake and cancer. The results may also explain the contradictions in the literature by pointing out that different fatty acids are not equivalent as far as cell growth and tumor promotion are concerned.
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FOOTNOTES |
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1 Supported by grants from the Cancer Research
Society of Montreal and the Canadian Diabetes Association. 
2 To whom requests for reprints should be
addressed, at Centre de Recherche du Centre Hospitalier de
l’Université de Montréal, Hôpital Notre-Dame,
Y-4603, 1560 Sherbrooke Est, Montréal, Québec,
Canada H2L 4M1. Phone: (514) 281-6000, ext. 6811; Fax:
(514) 896-4884; E-mail: marc.prentki{at}umontreal.ca
3 The abbreviations used are: FAS, fatty acid
synthase; FBS, fetal bovine serum; FFA, free fatty acid; PARP,
poly(ADP-ribose) polymerase; PI3-K, phosphatidylinositol 3-kinase.
Received 11/23/99. Accepted 9/20/00.
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S. M. Turpin, G. I. Lancaster, I. Darby, M. A. Febbraio, and M. J. Watt Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1341 - E1350. [Abstract] [Full Text] [PDF]
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S. Hardy, G. G. St-Onge, E. Joly, Y. Langelier, and M. Prentki Oleate Promotes the Proliferation of Breast Cancer Cells via the G Protein-coupled Receptor GPR40 J. Biol. Chem., April 8, 2005; 280(14): 13285 - 13291. [Abstract] [Full Text] [PDF]
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) was
assessed as described in "Materials and Methods." The results
represent the means ± SE of three independent
experiments performed in triplicate. All test values are significant
(P < 0.01) versus their
respective control situations.
