Maria E. Pasqualini

Effect of ω-3 and ω-9 fatty acid rich oils on lipoxygenases and cyclooxygenases enzymes and on the growth of a mammary adenocarcinoma model

BackgroundNutritional factors play a major role in cancer initiation and development. Dietary polyunsaturated fatty acids (PUFAs) have the ability to induce modifications in the activity of lipoxygenase (LOX) and cyclooxygenase (COX) enzymes that affect tumour growth. We studied the effect of two diets enriched in 6% Walnut and Peanut oils that are rich in ω-3 and ω9 PUFAs respectively on a murine mammary gland adenocarcinoma as compared with the control (C) that received commercial diet.ResultsPeanut oil enriched diet induced an increase in membrane arachidonic acid (AA) content and the cyclooxygenase enzyme derived 12-HHT (p < 0.05) and simultaneously showed decrease in 12-LOX, 15-LOX-2, 15-LOX-1 and PGE activities (p < 0.05) that corresponded to higher apoptosis and lower mitosis seen in this group (p < 0.05). Furthermore, Peanut oil group showed lower T-cell infiltration (p < 0.05), number of metastasis (p < 0.05) and tumour volume (p < 0.05) and longer survival rate compared to other groups.ConclusionsThe results of the present study showed that Peanut oil-enriched diet protects against mammary cancer development by modulating tumour membrane fatty acids composition and LOX and COX enzyme activities.

Basic aspects of tumor cell fatty acid-regulated signaling and transcription factors

This article reviews the current knowledge and experimental research about the mechanisms by which fatty acids and their derivatives control specific gene expression involved during carcinogenesis. Changes in dietary fatty acids, specifically the polyunsaturated fatty acids of the ω-3 and ω-6 families and some derived eicosanoids from lipoxygenases, cyclooxygenases, and cytochrome P-450, seem to control the activity of transcription factor families involved in cancer cell proliferation or cell death. Their regulation may be carried out either through direct binding to DNA as peroxisome proliferator-activated receptors or via modulation in an indirect manner of signaling pathway molecules (e.g., protein kinase C) and other transcription factors (nuclear factor kappa B and sterol regulatory element binding protein). Knowledge of the mechanisms by which fatty acids control specific gene expression may identify important risk factors for cancer and provide insight into the development of new therapeutic strategies for a better management of whole body lipid metabolism.

Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic Acid.

Numerous reports have demonstrated a tumor inhibitory effect of polyunsaturated fatty acids (PUFAs). However, the molecular mechanisms modulating this phenomenon are in part poorly understood. Here, we provide evidence of a novel antitumoral mechanism of the PUFA arachidonic acid (AA). In vivo and in vitro experiments showed that AA treatment decreased tumor growth and metastasis and increased apoptosis. Molecular analysis of this effect showed significantly reduced expression of a subset of antiapoptotic proteins, including BCL2, BFL1/A1, and 4-1BB, in AA-treated cells. We demonstrated that down-regulation of the transcription factor glioma-associated protein 1 (GLI1) in AA-treated cells is the underlying mechanism controlling BCL2, BFL1/A1, and 4-1BB expression. Using luciferase reporters, chromatin immunoprecipitation, and expression studies, we found that GLI1 binds to the promoter of these antiapoptotic molecules and regulates their expression and promoter activity. We provide evidence that AA-induced apoptosis and down-regulation of antiapoptotic genes can be inhibited by overexpressing GLI1 in AA-sensitive cells. Conversely, inhibition of GLI1 mimics AA treatments, leading to decreased tumor growth, cell viability, and expression of antiapoptotic molecules. Further characterization showed that AA represses GLI1 expression by stimulating nuclear translocation of NFATc1, which then binds the GLI1 promoter and represses its transcription. AA was shown to increase reactive oxygen species. Treatment with antioxidants impaired the AA-induced apoptosis and down-regulation of GLI1 and NFATc1 activation, indicating that NFATc1 activation and GLI1 repression require the generation of reactive oxygen species. Collectively, these results define a novel mechanism underlying AA antitumoral functions that may serve as a foundation for future PUFA-based therapeutic approaches.

Proaggregatory and procoagulant properties of three murine mammary gland tumor cell lines with different metastatic capabilities

We have investigated the in vitro proaggregatory and procoagulant properties of three murine tumor cell lines having different metastatic potentials. The characterization was carried out with appropriate procoagulant inhibitors and plasma deficient in factors VII and X. The proaggregatory properties of M2, M3 and MM3 cell lines increased according to their metastatic potentials. Their procoagulant activity were dependent on factor X. The prothrombotic abilities exhibited by neoplastic cells (NC), acting synergistically, might play a role in cancer dissemination.

Isologous and heterologous platelet aggregation induced by tumor cells from three murine mammary gland adenocarcinomas with different metastatic abilities

The addition of neoplastic cells (NC) isolated from murine mammary gland adenocarcinomas having moderate and high metastatic ability on in vitro heparinized mice platelet rich plasma (PRP) induced platelet aggregation. One non-metastatic line did not induce aggregation. The aggregatory effect was not correlated with the metastatic abilities. None of the three types of tumors did cause aggregation on whole blood or PRP of rats. These adenocarcinomas seem to be suitable models to study in vitro the interactions between platelets and tumor cells having metastatic and non-metastatic potentials.

The effects of ω−6 and ω−3 fatty-acids on early stages of mice DMBA submandibular glands tumorigenesis

The aim of this work was: to assess the impact of diets enriched in polyunsaturated fatty acids ω-3 and ω-6 families on the lipid profile of cell membrane and their effect on cycle regulation and apoptosis, evaluated by TP53 and Ki-67 expression in 9,10-dimethyl-1,2-benzanthracene (DMBA) induced tumor development in submandibular glands (SMG) in murine models. To generate tumorigenic changes, SMG mice in the experimental group were injected with 50μl of 0.5% of DMBA. Both control (no DMBA) and experimental groups of BALB/c mice were fed with: chia oil (ChO), rich in ω-3 fatty acid; corn oil (CO), rich in ω-6/ω-3 fatty acid; and safflower (SO) oil, rich in ω-6fatty acid. Results demonstrate novel differential effects of ω-3 and ω-6 PUFAs on the regulation of early tumorigenesis events in murine SMG injected with DMBA. This knowledge may help to develop chemoprotective treatments, therapeutic agents and health promotion and prevention activities in humans.