Cited by 118Edible Oils Quality and AnalysisHER2/EGFR in Cancer ResearchCancer, Lipids, and Metabolism

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Mediterranean Dietary Traditions for the Molecular Treatment of Human Cancer: Anti-Oncogenic Actions of the Main Olive Oils Monounsaturated Fatty Acid Oleic Acid (18:1n-9)

Menendez, Javier, Lupu, Ruth·2006·Current Pharmaceutical Biotechnology

DOI 10.2174/138920106779116900

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Abstract

The final proof about the specific mechanisms by which the different components of olive oil, the principal source of fat in a typical "Mediterranean diet", exert their potential protective effects on the promotion and progression of several human cancers requires further investigations. A recent discovery that dietary fatty acids can interact with the human genome by regulating the amount and/or activity of transcription factors has opened a whole new line of research aimed to molecularly corroborate the ant-cancer benefits of the olive oil-based Mediterranean diet and the underlying mechanisms. Our most recent findings reveal that oleic acid (OA; 18:1n-9), the main olive oil's monounsaturated fatty acid, can suppress the overexpression of HER2 (erbB-2), a well-characterized oncogene playing a key role in the etiology, invasive progression and metastasis in several human cancers. First, exogenous supplementation with physiological concentrations of OA significantly down-regulates HER2-coded p185(Her-2/neu) oncoprotein in human cancer cells naturally harboring amplification of the HER gene. Second, OA exposure specifically represses the transcriptional activity of the human HER2 gene promoter in tumor-derived cell lines naturally exhibiting HER2 gene amplification and p185(Her-2/neu) protein overexpression but not in cancer cells expressing physiological levels of HER2. Third, OA treatment induces the up-regulation of the Ets protein PEA3 (a transcriptional repressor of the HER2 gene promoter) solely in cancer cells naturally displaying HER2 gene amplification. Fourth, HER2 gene promoter bearing a PEA3 site-mutated sequence cannot be negatively regulated by OA, while treatment with OA fails to repress the expression of a human full-length HER2 cDNA controlled by a SV40 viral promoter. Fifth, OA-induced inhibition of HER2 promoter activity does not occur if HER2 gene-amplified cancer cells do no concomitantly exhibit high levels of Fatty Acid Synthase (FASN; Oncogenic antigen-519) as specific depletion of FASN, which itself similarly suppresses HER2 overexpression by inducing PEA3-dependent repression of HER2 gene promoter, strongly antagonizes the inhibitory effects of OA on HER2 gene promoter activity. Considering that OA treatment efficiently blocks FASN activity and down-regulates FASN protein expression, it is reasonable to suggest that an accumulation of supra-physiological concentrations of the FASN substrate malonyl-CoA, due to its reduced utilization by FASN in the presence of exogenous OA, appears to act as an indicator of "cell fuel" availability capable to suppress HER2 expression via formation of inhibitory "PEA3 protein-PEA3 DNA binding site" complexes on the endogenous HER2 promoter. Indeed, malonyl-CoA on its own dramatically decreases HER2 promoter activity, while OA or malonyl-CoA similarly up-regulates PEA3 gene promoter activity. This previously unrecognized ability of OA to directly affect the expression of a cluster of interrelated human cancer genes (i.e., HER2, FASN and PEA3) should open a new line of research aimed to explore the anti-cancer effects of OA. Certainly, an appropriate dietary intervention reproducing this prominent anti-oncogenic feature of the "Mediterranean diet" must be carried out in animal models and human pilot studies in the future. Only then we will know whether the old "Mediterranean dietary traditions" will become a new molecular approach in the management of cancer disease.

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Adherence to the Mediterranean diet in young male soccer players
Leão, C., Rocha‐Rodrigues, S., Machado, I., Lemos, J., Leal, S. M., & Nobarı, H. (2023) · BMC Nutrition · doi:10.1186/s40795-023-00761-6 · Cited by 12
“Their positive effects have been demonstrated in some pathologies, such as cardiovascular diseases/coronary heart disease, metabolic syndrome, diabetes mellitus type 2, breast cancer [55–58]as well as in weight control [59].”
Background
Oleic acid as modulator of oxidative stress in European sea bass (Dicentrarchus labrax) juveniles fed high dietary lipid levels
Martins, N., Moutinho, S., Magalhães, R., Pousão‐Ferreira, P., Oliva‐Teles, A., Perés, H., & Castro, C. (2023) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2023.110929 · Cited by 12
Angiotensin II type 2 receptor blockade inhibits fatty acid synthase production through activation of AMP-activated protein kinase in pancreatic cancer cells
McGhee, A., Sivarajah, M., Gong, Q., Lim, S., Chipitsyna, G. I., Yeo, C. J., & Arafat, H. A. (2011) · Surgery · doi:10.1016/j.surg.2011.06.002 · Cited by 12
Overexpressing TNF-Alpha in Pancreatic Ductal Adenocarcinoma Cells and Fibroblasts Modifies Cell Survival and Reduces Fatty Acid Synthesis via Downregulation of Sterol Regulatory Element Binding Protein-1 and Activation of Acetyl CoA Carboxylase
Zoubi, M. S. A., Chipitsyna, G. I., Saxena, S., Sarosiek, K., Gandhi, A. V., Kang, C. Y., Relles, D. M., Sendecki, J. A., Hyslop, T., Yeo, C. J., et al. (2013) · Journal of Gastrointestinal Surgery · doi:10.1007/s11605-013-2370-7 · Cited by 12
Guidelines, minimal requirements and standard of cancer care around the Mediterranean Area: Report from the Collaborative AROME (Association of Radiotherapy and Oncology of the Mediterranean Area) working parties
AROME (2010) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2010.03.007 · Cited by 11
“This can be attributed to many reasons, most important of which seems to be the Mediterranean diet [23–27].”
Background
Fatty acid intake and breast cancer in the Spanish multicase–control study on cancer (MCC-Spain)
Dierssen‐Sotos, T., Gómez‐Acebo, I., Palazuelos, C., et al. (2019) · European Journal of Nutrition · doi:10.1007/s00394-019-01977-8 · Cited by 11
A proteomic analysis of the functional effects of fatty acids in NIH 3T3 fibroblasts
Magdalon, J., Hatanaka, E., Romanatto, T., Rodrigues, H. G., Kuwabara, W. M. T., Scaife, C., Newsholme, P., & Curi, R. (2011) · Lipids in Health and Disease · doi:10.1186/1476-511x-10-218 · Cited by 10
Quantification of Phenolic Compounds in Olive Oils by Near-Infrared Spectroscopy and Multiple Regression: Effects of Cultivar, Hydroxytyrosol Supplementation, and Deep-Frying
Mehany, T., González-Sáiz, J. M., & Pizarro, C. (2025) · Antioxidants · doi:10.3390/antiox14060672 · Cited by 8
“Besides phenolic compounds, the unsaturated fatty acids (UFAs) in VOO, particularly oleic and linoleic acids, have been shown to impact cancer development and metastasis by suppressing the overexpression of the oncogene HER2 [14].”
Drupe Characters, Fatty Acids, Polyphenolic and Aromatic Profile of Olive Oil Obtained from “Oliva Bianca”, Minor Autochthonous Cultivar of Campania
Vaio, C. D., Graziani, G., Gaspari, A., et al. (2021) · Plants · doi:10.3390/plants10061119 · Cited by 8
Essential Fatty Acids—Biochemistry, Physiology and Clinical Significance
Das, U. N. (2011) · Springer eBooks · doi:10.1007/978-94-007-0495-4_4 · Cited by 9
Mechanisms of increased gastric protection after NSAID-administration in rats consuming virgin olive oil diets
Motilva, V., Sánchez‐Fidalgo, S., Barranco, M. D., Herrerías, J. M., & de la Lastra, C. A. (2008) · e-SPEN the European e-Journal of Clinical Nutrition and Metabolism · doi:10.1016/j.eclnm.2007.10.003 · Cited by 7
Role of Natural Fermented Olives in Health and Disease
Peres, C. M., Peres, C. M., & Malcata, F. X. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802309-9.00022-4 · Cited by 7
HPV-induced recurrent laryngeal papillomatosis: rationale for adjuvant fatty acid therapy.
Louw, L., & Claassen, A. (2008) · PubMed · Cited by 6
Unsaturated fatty acids differ between hepatic colorectal metastases and liver tissue without tumour in humans: Results from a randomised controlled trial of intravenous eicosapentaenoic and docosahexaenoic acids
Stephenson, J. A., Al‐Taan, O., Arshad, A. R., West, A. L., Calder, P. C., Morgan, B., Metcalfe, M. S., & Dennison, A. R. (2013) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2013.04.002 · Cited by 5
The protective role of olive oil against gibberellic acid-induced embryotoxicity at prenatal stages of mice
Amra, E.-S. A., Lashein, F. E.-D. M., Seleem, A. A., & Saleh, M. M. (2020) · The Journal of Basic and Applied Zoology · doi:10.1186/s41936-020-00182-y · Cited by 5
“Olive oil was documented as having anti-oncogenic activity and anti-cancer especially colorectal and breast cancer (Menendez and Lupu, 2006; Pelucchi et al., 2011) and decreases chronic disease such as cardiovascular diseases (CVD) (Ruiz-Canela and Martínez-González, 2011) and atherosclerosis (Kok…”
Background
Fruits
Mohammed, S. G. A. A., & Qoronfleh, M. W. (2020) · Advances in neurobiology · doi:10.1007/978-3-030-30402-7_10 · Cited by 5
Olive leaf extract green-formulated manganese nanoparticles: Characterization and antioxidant, cytotoxicity and anti-breast carcinoma properties
Feng, Y., & Yu, H. (2024) · Inorganic Chemistry Communications · doi:10.1016/j.inoche.2024.112376 · Cited by 4
Epigenetics/Epigenomics of Olive Oil and the Mediterranean Diet
Capurso, A., Crepaldi, G., & Capurso, C. A. (2018) · Practical issues in geriatrics · doi:10.1007/978-3-319-78084-9_7 · Cited by 3
Olea europaea
Lim, T. K. (2012) · Springer eBooks · doi:10.1007/978-94-007-4053-2_12 · Cited by 3
Elemental analysis of Moringa oleifera seeds by Laser Induced Breakdown Spectroscopy (LIBS) and its anti-cancer and anti-microbial studiesPreprint
Gondal, M. A. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.15.042663 · Cited by 3
Exploration of Medicinal Properties and Metabolite Diversity Between Different Petiole Types of Simarouba Glauca: A Nontargeted Metabolomics Approach
Kandaswamy, H., Kannathasan, M., Selvakumar, D., et al. (2024) · Environmental Quality Management · doi:10.1002/tqem.70009 · Cited by 2
Choline Based Surfactants Promote Cellular Uptake of Solid Lipid Nanoparticles into Lung and Breast Cancer Cells
Saadat, M., Jafari, S., Mahmoudian, M., Sarfraz, M., Khaleseh, F., Zakeri‐Milani, P., Mojarrad, J. S., & Valizadeh, H. (2024) · Current Nanoscience · doi:10.2174/0115734137308989240520053704 · Cited by 1
Nutritional Value and Physical Quality of Oral Nutritional Supplements Made from Purple Sweet Potatoes to Treat Malnutrition in Patients with Cancer
Kurniasari, F. N., Susetyowati, S., Hardianti, M. S., & Cempaka, A. R. (2023) · Current Nutrition & Food Science · doi:10.2174/1573401319666230608162235 · Cited by 1
Research Outreach Interdisciplinary Activity to classify olive oil blends integrating multicolor imaging, image processing, and machine learning
Abraham, A., & Balachandran, K. (2023) · Undergraduate Research · doi:10.58361/2766-3590.1062 · Cited by 1
The Impact of Olive Oil and Mediterranean Diet on the Prevention of Cardiovascular Diseases
Akram, M., Ansari, R., Akhter, N., Otekunrin, O. A., Zafar, S., Ishaque, M., Munir, N., Sciarra, L., My, G., Matarrese, E. C. G., et al. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.97146 · Cited by 1
Clinically relevant ex vivo fatty acid profiles from a lipid model for colorectal adenocarcinoma
Nel, A. (2007) · Cited by 1
Protective role of olive oil and its major component oleic acid in TNF-α induced remodeling subsequent to myocardial infarction in rats
Al‐Shudiefat, A. A. (2013) · Mspace (University of Manitoba) · Cited by 1
Cancers
Hoffman, R. M., & Gerber, M. (2011) · Wiley eBooks · doi:10.1002/9781118785027.ch12 · Cited by 1
Metabolic modeling of Hermetia illucens larvae resource allocation for high-value fatty acid productionPreprint
Grausa, K., Siddiqui, S. A., Lameyer, N., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.25.513765 · Cited by 1
Determination of Bioactive Components in 300°C Pyrolyzate of Extract from Oil-Tea Cake by Pyrolysis- GC/MS
Liu, Q.-M., Peng, W., Zhang, D., et al. (2010) · International Conference on Bioinformatics and Biomedical Engineering · doi:10.1109/icbbe.2010.5517799
“Moreover, there are abundant bioactive components in the benzene/ethanol extract or acetone extract of oil-tea cake, especially including ethyl oleate, 14-pentadecenoic acid, pentadecanoic acid, ethyl ester, 9-octadecenal, (z)-, (z)14tricosenyl formate, 3',5'-dimethoxyacetophenone, hexadecanoic acid, etc [14,15,16].”
Background
Efeitos dos inibidores da enzima ácido graxo sintase sobre apoptose e função mitocondrial de células não tumorigênicas
Rossato, F. A. (2014) · doi:10.47749/t/unicamp.2014.927718
Nuts as Part of a Whole Diet Approach to Cancer Prevention
Davis, P. A. (2010) · Springer eBooks · doi:10.1007/978-90-481-9800-9_9
Role of Omega-3 Fatty Acids in the Risk and Treatment of Breast Cancer
Janos, A. L., & Logomarsino, J. V. (2011) · Topics in Clinical Nutrition · doi:10.1097/tin.0b013e3182260ecf
Olive Oil Prevents Experimentally Induced Breast and Colon Carcinogenesis
Schwartz, B., & Madar, Z. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374420-3.00103-0

Authors: Menendez, J., & Lupu, R.
ORCID: Lupu, Ruth
Venue: Current Pharmaceutical Biotechnology
Publisher: Bentham Science Publishers Ltd.
Published: 2006-12-01
Volume: 7
Issue: 6
Pages: 495-502
ISSN: 1389-2010 (ISSN-L)
DOI: 10.2174/138920106779116900
OpenAlex: W2017365897
Cited by: 113
References: 0
Citations by year: 2026: 3 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 10 · 2019: 4 · 2018: 8 · 2017: 5 · 2016: 2 · 2015: 8 · 2014: 4 · 2013: 7 · 2012: 4
FWCI: 3.40
Type: journal article
Language: en
Open access: closed
Locations: Current Pharmaceutical Biotechnology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
Instituto de Salud Carlos III
National Cancer Institute (R01CA116623)
Topics: Physical Sciences › Chemistry › Organic Chemistry › Edible Oils Quality and Analysis
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords: oleic acid, olive oil, Mediterranean diet, HER2, HER2 amplification, PEA3, fatty acid synthase, transcriptional repression, malonyl-CoA, cancer prevention, dietary fatty acids, transcription factors, apoptosis, cell cycle arrest, metastasis, tumor angiogenesis
MeSH terms: Olive Oil, Antineoplastic Agents, Dietary Fats, Unsaturated, Fatty Acids, Essential, Humans, Neoplasm Proteins, Neoplasms, Plant Oils, Signal Transduction, Apoptosis, Erb-b2 Receptor Tyrosine Kinases, Oleic Acid, Diet, Mediterranean

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Mediterranean Dietary Traditions for the Molecular Treatment of Human Cancer: Anti-Oncogenic Actions of the Main Olive Oils Monounsaturated Fatty Acid Oleic Acid (18:1n-9)

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