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Refolo M.G.,National Institute For Digestive Diseases S Of Bellis | D'Alessandro R.,National Institute For Digestive Diseases S Of Bellis | Malerba N.,National Institute For Digestive Diseases S Of Bellis | Laezza C.,CNR Institute of Neuroscience | And 6 more authors.
Journal of Cellular Physiology | Year: 2015

Quercetin, the major constituent of flavonoid and widely present in fruits and vegetables, is an attractive compound for cancer prevention due to its beneficial anti proliferative effects, showing a crucial role in the regulation of apoptosis and cell cycle signaling. In vitro studies have demonstrated that quercetin specifically influences colon cancer cell proliferation. Our experiments, using human colon adenocarcinoma cells, confirmed the anti proliferative effect of quercetin and gave intriguing new insight in to the knowledge of the mechanisms involved. We observed a significant increase in the expression of the endocannabinoids receptor (CB1-R) after quercetin treatment. CB1-R can be considered an estrogen responsive receptor and quercetin, having a structure similar to that of the estrogens, can interact with CB1-R leading to the regulation of cell growth. In order to clarify the contribution of the CB1-R to the quercetin action, we investigated some of the principal molecular pathways that are inhibited or activated by this natural compound. In particular we detected the inhibition of the major survival signals like the PI3K/Akt/mTOR and an induction of the pro apoptotic JNK/JUN pathways. Interestingly, the metabolism of β-catenin was modified by flavonoid both directly and through activated CB1-R. In all the experiments done, the quercetin action has proven to be reinforced by anandamide (Met-F-AEA), a CB1-R agonist, and partially counteracted by SR141716, a CB1-R antagonist. These findings open new perspectives for anticancer therapeutic strategies. © 2015 Wiley Periodicals, Inc. Source


Notarnicola M.,National Institute for Digestive Diseases | Barone M.,University of Bari | Francavilla A.,University of Bari | Tutino V.,National Institute for Digestive Diseases | And 7 more authors.
Oncology Reports | Year: 2016

The statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and orlistat, an inhibitor of fatty acid synthase (FAS), inhibit tumor cell growth by restricting cholesterol and fatty acid synthesis, respectively. We previously demonstrated that an omega (ω)-3 polyunsaturated fatty acid (PUFA)- or olive oil-enriched diet reduced the polyp number and volume in ApcMin/+ mice. This phenomenon was associated with a significant inhibition of FAS and HMGCoAR, as well as an increase in the estrogen receptor (ER)β/α ratio. Herein, we evaluated the effect of lovastatin and orlistat on polyp development and ER expression in ApcMin/+ mice, in order to confirm previous data obtained with ω-3-PUFAs and olive oil. As expected, the use of lovastatin and orlistat significantly reduced HMGCoAR and FAS enzymatic activities and gene expression in colonic tissues, but did not affect the number of intestinal polyps, while there was a statistically significant reduction in polyp volume only in the mouse group treated with lovastatin. In the mice receiving orlistat, we observed a significant increase in cell proliferation in the polyp tissue, as well as enhanced expression of ERα. Moreover, the overexpression of ERα was associated with a statistically significant increase in PES1, Shh and Gli1 protein levels, considered ERα-related molecular targets. Source


Notarnicola M.,National Institute For Digestive Diseases S Of Bellis | Pisanti S.,University of Salerno | Tutino V.,National Institute For Digestive Diseases S Of Bellis | Bocale D.,University of Bari | And 6 more authors.
Genes and Nutrition | Year: 2011

Oleuropein (OL) and hydroxytyrosol (HT), the main olive oil polyphenols, possess anti-proliferative effects in vitro. Fatty acid synthase, a key anabolic enzyme of biosynthesis of fatty acids, plays an important role in colon carcinoma development. Our aim was to investigate whether gene expression of FAS, as well as its enzymatic activity, is regulated by HT and OL in two human colon cancer cell lines, as HT-29 and SW620. In addition, we investigated the effects of these polyphenols on growth and apoptosis in these cells. FAS gene expression and activity in treated HT-29 and SW620 cells were evaluated by real-time PCR and radiochemical assay, respectively. Cell growth and apoptosis, after polyphenols treatment, were measured by MTT test and flow cytometry, respectively. The inhibition of proliferation, detected after HT treatment, was mediated by an inhibition of FAS expression and its enzymatic activity in SW620 cells, while the anti-proliferative effect in HT-29 cells seems to be independent from FAS. OL exerted an anti-proliferative effect only on SW620 cells with a mechanism which excluded FAS. Olive oil polyphenols used were able to induce apoptosis in both cell lines studied. The increase of apoptosis in these cells was accompanied by the block of cell cycle in the S phase. This study demonstrates that HT and OL may induce anti-proliferative and pro-apoptotic effects only in certain human colorectal cancer cell types. These effects are FAS mediated only in SW620 cells after treatment with HT. © 2010 Springer-Verlag. Source


Barone M.,University of Foggia | Notarnicola M.,National Institute For Digestive Diseases S Of Bellis | Caruso M.G.,National Institute For Digestive Diseases S Of Bellis | Scavo M.P.,University of Bari | And 7 more authors.
Carcinogenesis | Year: 2014

The promotion and progression of carcinogenesis are susceptible to nutritional interventions aimed at counteracting cancer development. Lipid metabolism is essential in the onset and progression of tumours as well as for cancer cell survival. In the present study we tested the effects of diets enriched with natural compounds, such as olive oil and salmon oil, in mice that spontaneously develop intestinal polyps (ApcMin/+ mice). For this purpose we evaluated polyp number and volume, intestinal mucosa proliferation/apoptosis, oestrogen receptors (ERs) expression, fatty acid synthase (FAS) and 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase gene expression and enzymatic activity. As compared to the standard diet, the salmon oil-enriched diet, containing a high percentage of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) and, to a lesser extent, olive oil-enriched diet reduced polyp number and volume through a reduction of proliferation and a marked proapoptotic effect. These biological effects were mediated by an inhibition of FAS and HMGCoA reductase gene expression and activity and an increase of ERβ/ERα ratio. Our findings suggest that a proper dietary lifestyle could contribute to primary cancer prevention. Summary: Natural substances, components of Mediterranean Diet, may counteract intestinal polyp development through the modulation of metabolic pathways involving lipogenic enzymes and estrogen receptors. Our findings further support the idea that an appropriate dietary treatment is important in colon tumour prevention. Source


Notarnicola M.,National Institute For Digestive Diseases S Of Bellis | Miccolis A.,National Institute For Digestive Diseases S Of Bellis | Tutino V.,National Institute For Digestive Diseases S Of Bellis | Lorusso D.,National Institute For Digestive Diseases S Of Bellis | Caruso M.G.,National Institute For Digestive Diseases S Of Bellis
Lipids | Year: 2012

Lipoprotein lipase (LPL) is the crucial enzyme for intravascular catabolism of triglyceride-rich lipoproteins. Fatty acid synthase (FAS) is a key anabolic enzyme that catalyzes the terminal steps in the novo biosynthesis of 18:2n-6. The involvement of both LPL and FAS in tumor biology has been widely demonstrated in different studies and to verify whether there are regional differences in the expression of these enzymes in visceral adipose tissue from patients with colorectal cancer might be representative of events which sustain tumor growth. The objective of this study was to evaluate LPL and FAS activity and expression of their genes in adipose tissue adjacent to neoplasia and distant from it from patients operated for colorectal cancer. LPL enzymatic activity was evaluated by a fluorescent method and FAS activity by a radiometer assay. Reversetranscription and real-time PCR were used to detect mRNA levels of two enzymes. Our findings show a significant reduction in both LPL and FAS gene expression and activity levels in adipose tissue adjacent to tumor lesion compared to those detected in paired tissue distant from neoplasia. These results underline the influence of tumor microenvironment on lipid metabolism in adipose tissue, demonstrating a tumor-induced impairment in the formation and lipid storing capacity of adipose tissue in patients with colorectal cancer. © 2011 AOCS. Source

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