Docosahexaenoic Acid Induces Increases in [Ca2+]ivia Inositol 1,4,5-Triphosphate Production and Activates Protein Kinase Cγ and -δ via Phosphatidylserine Binding Site: Implication in Apoptosis in U937 Cells

Aires, Virginie; Hichami, Aziz; Filomenko, Rodolphe; Plé, Aude; Rébé, Cédric; Bettaieb, Ali; Khan, Naim Akhtar

doi:10.1124/mol.107.039792

Cited by 44 publications

(28 citation statements)

References 41 publications

(40 reference statements)

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“…This result supports previous findings obtained with DHA in our and other laboratories using different cellular models [6,57,58]. However, the molecular factors which may be modulated by DHA in the apoptotic cascades of lung cancer cells remain to be elucidated.…”

Section: Discussionsupporting

confidence: 94%

Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression

et al. 2008

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Different agents able to modulate apoptosis have been shown to modify the expression of the MAP-kinase-phosphatase-1 (MKP-1). The expression of this phosphatase has been considered a potential positive prognostic factor in lung cancer, and smoke was shown to reduce the levels of MKP-1 in ferret lung. Our aim was to assess whether the n-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), known to inhibit the growth of several cancer cells mainly inducing apoptosis, may exert pro-apoptotic effect in lung cancer cells by modifying MKP-1 expression. We observed that DHA increased MKP-1 protein and mRNA expression and induced apoptosis in different lung cancer cell lines (mink Mv1Lu adenocarcinoma cells, human A549 adenocarcinoma and human BEN squamous carcinoma cells). We inhibited the pro-apoptotic effect of DHA by treating the cells with the phosphatase inhibitor Na(3)VO(4) or by silencing the MKP-1 gene with the specific siRNA. This finding demonstrated that the induction of apoptosis by DHA involved a phosphatase activity, specifically that of MKP-1. DHA reduced also the levels of the phosphorylated MAP-kinases, especially ERK1/2 and p38. Such an effect was not observed when the MKP-1 gene was silenced. Altogether, the data provide evidence that the DHA-induced overexpression of MKP-1 and the resulting decrease of MAP-kinase phosphorylation by DHA may underlie the pro-apoptotic effect of this fatty acid in lung cancer cells. Moreover, they support the hypothesis that DHA may exert chemopreventive action in lung cancer.

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Section: Discussionsupporting

confidence: 94%

Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression

et al. 2008

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“…Similar results were obtained for different FA, as docosahexaenoic acid (DHA), arachidonic acid (AA) or LA, in several cell lines [30][31][32][33][34]. In addition, according to previous reports, such an increase was found to be concentration-dependent for the three FA tested [30,31].…”

Section: Discussionsupporting

confidence: 73%

Oleic Acid Versus Linoleic and α-Linolenic Acid. Different Effects on Ca2+ Signaling in Rat Thymocytes

Carrillo¹,

Cavia²,

Alonso-Torre³

2011

Cell Physiol Biochem

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Background: Oleic acid is the principal fatty acid of olive oil composition and is reported to play a crucial role in its healthy aspects. However, the detailed mechanism of action is poorly understood. Aims: This study aims to elucidate the role of oleic acid in calcium signaling in rat thymocytes, in comparison to linoleic and linolenic acid. Methods: Fatty acids were applied to thymocytes isolated from wistar rats and loaded with Fura-2 to measure calcium signals. Results: The main results showed a concentration-dependent increase in [Ca²⁺]_i induced by the 3 fatty acids. Raising the number of unsaturations resulted in greater increases. Two different pathways contributed to the increase induced by the polyunsaturated fatty acids: an IP₃- independent release from the thapsigargin-sensitive stores and an extracellular calcium entry by econazole and nifedipine-insensitive channels. However, the OA-induced increases in [Ca²⁺]_i seemed to be due mostly to the Ca²⁺ recruited from the intracellular stores. Conclusion: This study demonstrates that the fatty acids tested induce increases in [Ca²⁺]_i in rat thymocytes, with differences in close relation to the degree of unsaturation. Such differences could be responsible for their different physiological action.

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“…Subsequently, we investigated CCR3 signaling pathways in terms of calcium mobilization and phosphorylation of ERK. In contrast to a previous report that showed a DHA-induced calcium influx in U937 cells [27], DHA or LA (each 100 µ M ) failed to induce a calcium influx in eosinophils (data not shown). As shown in figure 5b, eotaxin-evoked calcium influx was significantly inhibited by pretreatment with DHA but not by LA.…”

Section: Resultscontrasting

confidence: 52%

“…Therefore, it is suggested that DHA-induced apoptosis is mediated through the caspase-3 pathway, at least in part. Indeed, DHA can activate caspase-3 activity in other types of cells, such as monocytes [29], Jurkat cells [30], and U937 cells [27]. …”

Section: Discussionmentioning

confidence: 99%

Docosahexaenoic Acid Exerts Anti-Inflammatory Action on Human Eosinophils through Peroxisome Proliferator-Activated Receptor-Independent Mechanisms

Tanigai

Ueki²,

Kihara³

et al. 2012

Int Arch Allergy Immunol

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Background: Despite the fact that previous studies have indicated the significant roles of polyunsaturated fatty acids (PUFAs) in the immune system through peroxisome proliferator-activated receptor alpha (PPARα) and PPARγ, the biological functions and the mechanisms of action in eosinophils are poorly understood. Methods: We investigated the functional effects of docosahexaenoic acid (DHA, n-3 PUFA) on human peripheral blood eosinophils, using in vitro systems to test the hypothesis that DHA negatively regulates eosinophil mechanisms through PPARα and PPARγ. Results: Eosinophil apoptosis that spontaneously occurs under normal culture conditions was accelerated in the presence of DHA. In addition, eotaxin-directed eosinophil chemotactic responses were inhibited by pretreatment with DHA, disturbing both the velocity and the directionality of the cell movement. Pharmacological manipulations with specific antagonists indicated that the effects of DHA were not mediated through PPARα and PPARγ, despite the presence of these nuclear receptors. DHA also induced Fas receptor expression and caspase-3 activation that appears to be associated with a proapoptotic effect of DHA. Further, DHA rapidly inhibited the expression of eotaxin receptor C-C chemokine receptor 3 and eotaxin-induced calcium influx and phosphorylation of extracellular signal-regulated kinase. Interestingly, these inhibitory effects were not observed with linoleic acid (n-6 PUFA). Conclusions: The data might explain one of the mechanisms found in previous research showing the favorable effects of n-3 PUFA supplementation on allergic diseases, and provide novel therapeutic strategies to treat eosinophilic disorders.

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Docosahexaenoic Acid Induces Increases in [Ca²⁺]_ivia Inositol 1,4,5-Triphosphate Production and Activates Protein Kinase Cγ and -δ via Phosphatidylserine Binding Site: Implication in Apoptosis in U937 Cells

Cited by 44 publications

References 41 publications

Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression

Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression

Oleic Acid Versus Linoleic and α-Linolenic Acid. Different Effects on Ca<sup>2+</sup> Signaling in Rat Thymocytes

Docosahexaenoic Acid Exerts Anti-Inflammatory Action on Human Eosinophils through Peroxisome Proliferator-Activated Receptor-Independent Mechanisms

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