Regulation of human lymphocyte proliferation by fatty acids

In the present study, the effect of increasing concentrations of palmitic (PA, C16:0), stearic (SA, C18:0), oleic (OA, C18:1, n-9), linoleic (LA, C18:2n-6), docosahexaenoic (DHA, C22:6 n-3) and eicosapentaenoic (EPA, C20:5 n-3) acids on lymphocyte proliferation was investigated. The maximal non-toxic concentrations of these fatty acids for human lymphocytes in vitro were determined. It was also evaluated whether these fatty acids at non-toxic concentrations affect IL-2 induced lymphocyte proliferation and cell cycle progression. OA and LA at 25 microM increased lymphocyte proliferation and at higher concentrations (75 microM and 100 microM) inhibited it. Both fatty acids promoted cell death at 200 microM concentration. PA and SA decreased lymphocyte proliferation at 50 microM and promoted cell death at concentrations of 100 microM and above. EPA and DHA decreased lymphocyte proliferation at 25 and 50 microM being toxic at 50 and 100 microM, respectively. PA, SA, DHA and EPA decreased the stimulatory effect of IL-2 on lymphocyte proliferation, increasing the percentage of cells in G1 phase and decreasing the proportion of cells in S and G2/M phases. OA and LA caused an even greater pronounced effect. The treatment with all fatty acids increased neutral lipid accumulation in the cells but the effect was more pronounced with PA and DHA. In conclusion, PA, SA, DHA and EPA decreased lymphocyte proliferation, whereas OA and LA stimulated it at non-toxic concentrations.     

Oleic acid promotes migration on MDA-MB-231 breast cancer cells through an arachidonic acid-dependent pathway

An association between dietary fatty, obesity and an increased risk of developing breast cancer has been suggested. In breast cancer cells, free fatty acids (FFAs) mediate biological effects including cell proliferation and ERK1/2 activation. However, the contribution of FFAs to tumor progression and metastasis through the regulation of cell migration has not been studied. We demonstrated here that stimulation on MDA-MB-231 breast cancer cells with oleic acid (OA) promotes an increase in focal adhesion kinase (FAK) phosphorylation, as revealed by site-specific antibodies that recognize the phosphorylation state of FAK at tyrosine-397 (Tyr-397), Tyr-577 and in vitro kinase assays. OA also promotes the migration of MDA-MB-231 cells. Treatment with Gi/Go proteins, phospholipase C (PLC), lipoxygenases (LOXs) and Src inhibitor prevents FAK phosphorylation and cell migration. In summary, our findings delineate a new signal transduction pathway, where OA mediates the production of arachidonic acid (AA), and then AA metabolites mediate FAK phosphorylation and cell migration in MDA-MB-231 breast cancer cells.     

Identification of genes regulated by oleic acid in Jurkat cells by suppressive subtractive hybridization analysis

In this study, the effect of oleic acid (50 microM) on gene expression of Jurkat cells (human T lymphocytes cell line) was examined using the suppressive subtractive hybridization approach. This technique allowed us to identify genes with higher or lower expression after cell treatment with oleic acid as compared to untreated cells. Oleic acid upregulated the expression of the translation elongation factor alpha 1 and ATP synthase 8 and downregulated gp96 (human tumor rejection antigen gp96), heat-shock protein 60 and subtilisin-like protein 4. These results suggest that oleic acid, at plasma physiological concentration, can regulate the expression of important genes to maintain the machinery that ensures cell functioning.     

Polyunsaturated fatty acids potentiate interleukin-1-stimulated arachidonic acid release by cells overexpressing type IIA secretory phospholipase A2.

By analyzing human embryonic kidney 293 cell transfectants stably overexpressing various types of phospholipase A2 (PLA2), we have shown that polyunsaturated fatty acids (PUFAs) preferentially activate type IIA secretory PLA2 (sPLA2-IIA)-mediated arachidonic acid (AA) release from interleukin-1 (IL-1)-stimulated cells. When 293 cells prelabeled with 13H]AA were incubated with exogenous PUFAs in the presence of IL-1 and serum, there was a significant increase in [3H]AA release (in the order AA > linoleic acid > oleic acid), which was augmented markedly by sPLA2-IIA and modestly by type IV cytosolic PLA2 (cPLA2), but only minimally by type VI Ca2(+)-independent PLA2, overexpression. Transfection of cPLA2 into sPLA2-IIA-expressing cells produced a synergistic increase in IL-1-dependent [3H]AA release and subsequent prostaglandin production. Our results support the proposal that prior production of AA by cPLA2 in cytokine-stimulated cells destabilizes the cellular membranes, thereby rendering them more susceptible to subsequent hydrolysis by sPLA2-IIA.     

Retinoic acid and ascorbic acid act synergistically in inhibiting human breast cancer cell proliferation

BACKGROUND: Breast cancer is an increasingly common malignancy. Several vitamins such as retinoic acid (RA), ascorbic acid (AA), vitamin D and vitamin E are known to prevent the development and progression of breast cancer. OBJECTIVE: We sought to determine whether RA and AA together (RA+AA) acted synergistically in blocking the proliferation of human breast cancer cells. To elucidate the mechanism by which RA+AA inhibited breast carcinoma proliferation, we then evaluated the gene expression profiles of the treated and untreated cells by radioactive cDNA microarray analysis. METHODS: We cultured the human breast cancer cell line MCF-7 for 3 days with 100 nM RA and/or 1 mM AA, counted the cell numbers and harvested the total RNAs for cDNA microarray analysis. RESULTS: RA, AA and RA+AA reduced MCF-7 cell proliferation by 20.7%, 23.3% and 75.7% relative to the untreated cell proliferation, respectively. The synergistic ratio of RA and AA was 1.72. The MCF-7 gene expression profiles showed that 29 genes were up-regulated and 38 genes were down-regulated after RA+AA treatment. The nature of these genes suggests that the mechanism by which RA and AA act synergistically in inhibiting human breast cancer cell proliferation may involve the expression of genes that induce differentiation and block proliferation, and the up-regulation of antioxidant enzymes and proteins involved in apoptosis, cell cycle regulation and DNA repair. CONCLUSION: Combined treatment with RA and AA inhibits the proliferation of human breast cancer cells by altering their gene expression related to antioxidation processes as well as the proliferation inhibitory pathway.     

Prostaglandin E precursor fatty acids inhibit human IL-2 production by a prostaglandin E-independent mechanism

Essential fatty acids, from which PG derive, can participate in development and regulation of immune responses and have been shown to suppress inflammation and tissue injury in animal models. In this report, we investigate the effects of the immediate (DGLA, precursor to PGE1), arachidonic acid (AA, PGE precursors, dihomogamma linolenic acid (DGLA, precursor to PGE1), arachidonic acid (AA, precursor to PGE2), and eicosapentaenoic acid (EPA, precursor to PGE3) on IL-2 production by PHA-stimulated human PBMC. DGLA and AA inhibited IL-2 production in a dose-dependent manner: half-maximal inhibition was obtained by using the fatty acids at the dose of 10 micrograms/ml without significant effects on cell viability. EPA inhibited IL-2 production by PBMC of only some donors. Incubation of cells in the presence of oleic, stearic, and palmitic acids, which are not PG precursors, did not affect mitogen-induced IL-2 production. A progressive increase in incorporation of DGLA into cellular lipids was observed over a 48-h incubation period. IL-2 production was reduced also when PBMC were pretreated overnight with DGLA or AA and washed before exposure to PHA. Whereas addition of the cyclo-oxygenase inhibitor, indomethacin, at the time of mitogenic stimulation led to increased IL-2 production and prevented mitogen- and fatty acid-induced increases in PGE release, it had no significant effect on the capacity of the fatty acids to suppress IL-2 production. Time course experiments showed that DGLA and AA inhibited IL-2 production even at times of minimal or no PGE release by the treated cultures. Moreover, DGLA and AA inhibited IL-2 production by the human leukemia T cell line Jurkat which, when appropriately induced, is able to release high levels of IL-2 in the absence of accessory cells and measurable PGE production. Taken together, these data indicate that essential fatty acids inhibit IL-2 production directly without conversion into their cyclo-oxygenase pathway products, and suggest that human lymphocyte function may be altered profoundly by small changes in their fatty acid profile.     

Oleic acid and adipokines synergize in inducing proliferation and inflammatory signalling in human vascular smooth muscle cells

In the context of obesity, perivascular fat produces various adipokines and releases free fatty acids, which may induce inflammation and proliferation in the vascular wall. In this study we investigated how adipokines, oleic acid (OA) and the combined treatment regulate human vascular smooth muscle cell (hVSMC) proliferation and migration and the underlying signalling pathways. Adipocyte‐conditioned media (CM) generated from human adipocytes induces a prominent proliferation and migration of hVSMC. Autocrine action of adiponectin totally abolishes CM‐induced proliferation. Furthermore, OA but not palmitic acid induces proliferation of hVSMC. CM itself does not contain fatty acids, but CM in combination with OA markedly enhances proliferation of hVSMC in a synergistic way. Both the nuclear factor (NF)‐κB and the mammalian target of rapamycin (mTOR) pathway were synergistically activated under these conditions and found to be essential for hVSMC proliferation. Expression of iNOS and production of nitric oxide was only enhanced by combined treatment inducing a marked release of VEGF. Combination of OA and VEGF induces an additive increase of hVSMC proliferation. We could show that the combination of CM and OA led to a synergistic proliferation of hVSMC. Expression of iNOS and production of nitric oxide were only enhanced under these conditions and were paralleled by a marked release of VEGF. These results suggest that the combined elevated release of fatty acids and adipokines by adipose tissue in obesity might be critically related to hVSMC dysfunction, vascular inflammation and the development of atherosclerosis.     

Low-dose anisomycin is sufficient to alter the bio-behaviors of Jurkat T cells

Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus. It has been found that a quite low dose of anisomycin is sufficient to block proliferation of primary T lymphocytes. The focus of this study is to explore the possibility of anisomycin to treat human acute leukemia Jurkat T cells in vitro. The results indicated that the low dose of anisomycin could significantly inhibit the colony formation of Jurkat T cells and elevate the inhibition rate of Jurkat T cell growth along with its increasing concentrations. Jurkat T cell cycle was blocked into S-phase by anisomycin. Consistent with the increased proportion of sub-G1 phase, anisomycin promoted Jurkat T cell apoptosis. The CD69 and CD25 expression on the surface of Jurkat T cells was also down-regulated prominently along with the enhancing concentrations of anisomycin, followed by the decreased production of IL-4, IL-10, IL-17, TGF-β and IFN-γ, and the down-regulated expression of phosphorylated-ERK1/2. The results suggest that the suppressive effect of anisomycin on Jurkat T cell growth may be related to inhibiting TGF-β production and ERK1/2 activation, arresting the cell cycle at S-phase and promoting the apoptosis of Jurkat T cells.     

Arachidonic acid-containing phosphatidylcholine inhibits lymphocyte proliferation and decreases interleukin-2 and interferon-gamma production from concanavalin A-stimulated rat lymphocytes

The proliferation of concanavalin A (Con A)-stimulated rat lymphocytes was markedly inhibited by phosphatidylcholine containing arachidonic and stearic acids (PC(A-S)), but not by phosphatidylcholine containing oleic and stearic acids or phosphatidylinositol containing arachidonic and stearic acids. The concentration of PC(A-S) which inhibited Con A-stimulated proliferation by 50% was 31 microM and near total inhibition was observed at 154 microM . Phosphatidylserine containing only oleic acid enhanced proliferation by 37% at a concentration of 31 microM , but phosphatidylethanolamine and phosphatidylcholine containing only oleic acid did not affect proliferation at this concentration. It is concluded that both the head group and the fatty acid composition contribute to the influence of phospholipids on lymphocyte proliferation. The effects of PC(A-S) on T-lymphocyte responses were investigated further. In parallel with the inhibition of proliferation PC(A-S) caused a concentration-dependent decrease in the production of the Th1-type cytokines interleukin (IL)-2 and interferon (IFN)-gamma; inhibition of cytokine production was >85% at the highest concentration of PC(A-S) used (154 microM ). Production of the Th2-type cytokines IL-4 and IL-10 was not affected. The possible role of prostaglandins in mediating the effects of PC(A-S) was examined by adding indomethacin into the medium and the participation of lipid peroxidation was examined by adding vitamin E and vitamin C. Indomethacin and vitamin E did not affect the inhibition caused by PC(A-S) but vitamin C caused a partial reversal. It is concluded that inhibition of T-lymphocyte proliferation by phospholipids involves both the head group and the fatty acyl chains, that this inhibition is not mediated by prostaglandins but may involve some form of oxidant stress and that some phospholipids (e.g., PC(A-S)) can markedly influence cytokine profiles.     

Modulatory effect of linoleic and oleic acid on cell proliferation and lipid metabolism gene expressions in primary bovine satellite cells

This study was performed to elucidate the effects of linoleic acid (LA), oleic acid (OA) and their combination (LA?+?OA) on cell proliferation, apoptosis, necrosis, and the lipid metabolism related gene expression in bovine satellite cells (BSCs), isolated from bovine muscles. Cell viability was significantly increased with the OA and LA treatment. Furthermore, LA?+?OA enhanced cell proliferation in a dose-dependent manner (10 to 100?µM), whereas it lowered at 250?µM. In addition, a cell-cycle analysis showed that 100?µM of LA and OA markedly decreased the G0/G1 phase proportion (62.58% and 61.33%, respectively), compared to controls (68.02%), whereas the S-phase cells’ proportion was increased. The ratio of G2/M phase cells was not significantly different among the groups. Moreover, analyses with AO/EtBr staining showed that no apoptosis occurred. Necrosis were determined by flow cytometry using Annexin V-FITC/PI staining which revealed no early apoptosis in the cells pretreated with LA or OA, but occurred in the LA?+?OA group. We also analyzed the mRNA expression of lipid metabolizing genes such as peroxisome proliferator receptor alfa (PPARα), peroxisome proliferator receptor gamma (PPARγ), acyl-CoA oxidase (ACOX), lipoprotein lipase (LPL), carnitine palmitoyl transferase (CPT-1), and fatty-acid binding protein4 (FABP4), which were upregulated in LA or OA treated cells compared to the control group. In essence, LA and OA alone promote the cell proliferation without any apoptosis and necrosis, which might upregulate the lipid metabolism related gene expressions, and increase fatty-acid oxidation in the BSCs’ lipid metabolism.     

Effect of non-esterified fatty acids on bovine granulosa cell steroidogenesis and proliferation in vitro

In high-yielding dairy cows, the negative energy balance (NEB) during the first weeks post partum may influence dominant follicle growth and steroidogenesis. Since non-esterified fatty acid (NEFA) concentrations are elevated during NEB and are shown to be toxic for several cell types, we investigated the individual and combined effects of the three main NEFA's on granulosa cell proliferation and steroidogenesis in vitro. Granulosa cells from large follicles were cultured for two days in serum free medium in the presence of palmitic (C16:0) (PA), stearic (C18:0) (SA) and/or oleic acid (C18:1) (OA). Addition of 150, 300 or 500 microM of PA and SA inhibited cell proliferation (P<0.05) while OA only elicited such an effect at 500 microM (P<0.01). In the combination treatment (150 microM of each fatty acid), cell numbers were also reduced (P<0.01). These inhibitory effects on cell number are partly due to the induction of apoptosis by these NEFA's, as was demonstrated by annexin V-FITC/propidium iodide staining of the granulosa cells. Oestradiol-17beta production was stimulated by all doses of PA, by 300 and 500 microM of SA and by 500 microM of OA (P<0.05). Combined treatment with 150 microM of each fatty acid also stimulated oestradiol-17beta production per 10(4) cells (P<0.05). We can conclude that PA, SA and to a lesser degree OA modulate granulosa cell proliferation and steroidogenesis in vitro. These effects may be involved in the occurrence of ovarian dysfunction during the postpartum period in high-yielding dairy cows.     

Acyl-CoA synthetase 2 overexpression enhances fatty acid internalization and neurite outgrowth

During neurodevelopment neurons increase phospholipid synthesis to generate additional plasma membrane that makes up the growing neurites. Compared with most cell types, neurons contain a high percentage of the polyunsaturated fatty acids (PUFAs) arachidonic acid (AA) and docosahexaenoic acid (DHA). By utilizing PC12 cell lines as a model neuronal cell line, we examined the internalization rate of AA, DHA, and non-essential oleic acid (OA), as well as their effects on neurite outgrowth. When wild type cells were differentiated, the rate of AA and DHA internalization increased 50% more than the rate of OA internalization. When media were supplemented with AA or DHA, the average neurite length was increased by approximately 40%, but supplementation with the same amount of OA had no effect. We also increased the levels of acyl-CoA synthetase-1 (ACS1) and ACS2 proteins to determine whether they contribute to PUFA internalization or neurite outgrowth. Overexpression of ACS1 increased the rate of OA internalization by 55%, and AA and DHA uptake was increased by 25%, but there was no significant change in neurite outgrowth. In ACS2-overexpressing cells, in contrast, the rate of OA internalization increased by 90%, AA by 115%, and DHA by 70%. The average aggregate neurite length in ACS2-overexpressing cells was increased by approximately 40% when the media were supplemented with PUFAs, but there was no change with OA supplementation. Taken together, these results support the hypotheses that ACSs are rate-limiting for fatty acid internalization and that ACS2 enhances neurite outgrowth by promoting PUFA internalization.     

Elevated expression of the CD4 receptor and cell cycle arrest are induced in Jurkat cells by treatment with the novel cyclic dinucleotide 3',5'-cyclic diguanylic acid

The effect of the novel, naturally occurring nucleotide cyclic diguanylic acid (c-di-GMP) on the lymphoblastoid CD4+ Jurkat cell line was studied. When exposed to 50 microM c-di-GMP, Jurkat cells exhibited a markedly elevated expression of the CD4 receptor of up to 6.3-fold over controls. C-di-GMP also causes blockage of the cell cycle at the S-phase, characterized by increased cellular thymidine uptake, reduction in G2/M-phase cells, increase in S-phase cells and decreased cell division. Additionally c-di-GMP naturally enters these cells and binds irreversibly to the P21ras protein. The effects described appear to be unique for c-di-GMP.     

MiR-522-3p inhibits proliferation and activation by regulating the expression of SLC31A1 in T cells

We investigated the role of miR-522-3p in thymoma-associated myasthenia gravis (TAMG), and the mechanism of action in T cells. The miR-522-3p expression in normal serum, non-thymoma MG patient serum and TAMG patient serum and tissues was detected by quantitative real-time PCR (qRT-PCR), respectively. We assessed miR-522-3p expression in Jurkat cells and human CD4⁺ T cells after activation by anti-CD3 and anti-CD28 using qRT-PCR. The viability, proliferation, cycle distribution and the levels of CD25, CD69, interleukin-2 (IL-2) and IL-10 in transfected Jurkat cells were detected by Cell counting kit-8, 5-ethynyl-2′-deoxyuridine (EdU), flow cytometry, qRT-PCR, respectively. Targeting relationships of miR-522-3p and SLC31A1 were predicted and validated by bioinformatics analysis and dual-luciferase reporter. The viability, proliferation, cycle distribution and the levels of SLC31A1, CD25, CD69, IL-2 and IL-10 in transfected Jurkat cells were detected by above methods and western blot. The miR-522-3p expression was declined in TAMG and activated T cells. MiR-522-3p inhibitor promoted cell viability, EdU positive cells, cycle progression, and the level of CD25, CD69, IL-2 and IL-10 in Jurkat cells, while the effect of miR-522-3p mimic was the opposite. SLC31A1 was targeted by miR-522-3p, and miR-522-3p inhibited SLC31A1 expression. Overexpressed SLC31A1 reversed the inhibitory effects of miR-522-3p mimic on cell viability, EdU positive cell, cycle progression, and the levels of IL-2 and IL-10 in transfected Jurkat cells. MiR-522-3p expression was down-regulated in TAMG, and miR-522-3p inhibited proliferation and activation by regulating SLC31A1 expression in T cells.

     

Inhibitors of IL-2 production and IL-2 receptor expression in human leukemic T-cell line, Jurkat

1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a protein kinase inhibitor, suppressed interleukin 2 (IL-2) production and IL-2 receptor (IL-2R) expression of the human leukemic T-cell line, Jurkat, induced by 12-O-tetradecanoyl-phorbol-13-acetate and phytohemagglutinin-P. This effect was significant at 5 microM H-7 without loss of cell viability. Such activity was not observed with N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA 1004), a potent inhibitor of cGMP- and cAMP-dependent kinases, and a weak inhibitor of Ca2+-phospholipid-dependent protein kinase (protein kinase C). These findings suggest that protein kinase C is more closely associated with IL-2 receptor expression and IL-2 production of T cells than cGMP- or cAMP-dependent kinases. In addition, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a calmodulin inhibitor, suppressed both IL-2 production and IL-2R expression. Cycrosporin A (Cy A), a potent immunosuppressive drug, markedly inhibited IL-2 production of Jurkat cells whereas it did not affect the IL-2R expression. Thus, the mechanism of action of Cy A appears to differ from that of the protein kinase inhibitor, H-7, and the calmodulin inhibitor, W-7.     

Arachidonic acid-induced IL-6 expression is mediated by PKC alpha activation in osteoblastic cells

There are several pieces of evidence supporting the important role that essential fatty acids (EFAs) and their metabolites play in regulating calcium and bone metabolism, and their relevance to the pathobiology of bone disease, with particular reference to modulating effects on cytokines. We found that arachidonic acid (AA) triggers a cell signal in osteoblasts and leads to the expression of IL-6. To explore the biochemical pathways involved in AA induction of cytokine gene expression, we evaluated the potential protein kinase C (PKC) dependent mechanism accounting for the AA effect on IL-6 gene expression. The osteoblast-like cell line MG-63 was pretreated with calphostin C, a PKC inhibitor, or phorbol 12-myristate 13-acetate (PMA) for an extended period, a condition which causes PKC downregulation, and subsequently with AA. After these treatments, IL-6 gene expression was no longer evident. We also showed that PKC and, in particular, PKC alpha, which are both recruited to the particulate fraction, undergo proteolysis and autophosphorylation; all of these steps are required for PKC activation and, subsequently, for AA-induced signaling. It is interesting that other unsaturated fatty acids, such as oleic acid (OA) or eicosapentaenoic acid (EPA), are unable to induce either PKC activation or IL-6 gene expression.     

Effects of fatty acids on angiogenic activity in the placental extravillious trophoblast cells

Fatty acids regulate angiogenesis although no such information is available in first trimester placental trophoblast cells despite the fact that angiogenesis is a critical step involving these cells in early placentation. We investigated effects of different fatty acids on angiogenesis, their uptake and metabolism and expression of lipid metabolic genes in first trimester placental trophoblast cells using HTR-8/SVneo cell line. Fatty acid uptake by these cells exhibited a saturable kinetics. Uptake of AA was consistently greater compared with that of EPA and DHA throughout the incubation period of 180 min. Use of triacsin C, an inhibitor of acyl-CoA synthetase, significantly inhibited fatty acid uptake as well as fatty acid induced cell proliferation in these cells. Angiogenic effect (as measured by tube formation) of these fatty acids was in the following order DHA>EPA>AA>OA. Angiogenic effect of these fatty acids (AA, EPA, OA) was significantly decreased in ANGPTL4 knocked down cells, indicating ANGPTL4 may be involved at least in part in fatty acid induced angiogenesis. In addition, these fatty acids altered expression of several lipid metabolic genes such as ADRP, FABP4, FABP3, and COX-2 those are involved in angiogenesis. All these data suggest that fatty acids regulate angiogenic processes in these cells via different mechanisms.     

Leptin reverts pro-apoptotic and antiproliferative effects of α-linolenic acids in BCR-ABL positive leukemic cells: involvement of PI3K pathway

It is suspected that bone marrow (BM) microenvironmental factors may influence the evolution of chronic myeloid leukaemia (CML). In this study, we postulated that adipocytes and lipids could be involved in the progression of CML. To test this hypothesis, adipocytes were co-cultured with two BCR-ABL positive cell lines (PCMDS and K562). T cell (Jurkat) and stroma cell (HS-5) lines were used as controls. In the second set of experiments, leukemic cell lines were treated with stearic, oleic, linoleic or α-linolenic acids in presence or absence of leptin. Survival, proliferation, leptin production, OB-R isoforms (OB-Ra and OB-Rb), phosphoinositide 3-kinase (PI3k) and BCL-2 expression have been tested after 24h, 48h and 72h of treatment. Our results showed that adipocytes induced a decrease of CML proliferation and an increase in lipid accumulation in leukemic cells. In addition, CML cell lines induced adipocytes cell death. Chromatography analysis showed that BM microenvironment cells were full of saturated (SFA) and monounsaturated (MUFA) fatty acids, fatty acids that protect tumor cells against external agents. Stearic acid increased Bcl-2 expression in PCMDS, whereas oleic and linoleic acids had no effects. In contrast, α-linolenic acid decreased the proliferation and the survival of CML cell lines as well as BCL-2 and OB-R expression. The effect of α-linolenic acids seemed to be due to PI3K pathway and Bcl-2 inhibition. Leptin production was detected in the co-culture medium. In the presence of leptin, the effect of α-linolenic acid on proliferation, survival, OB-R and BCl-2 expression was reduced.