Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-κB

Menéndez, Javier A.; Mehmi, Inderjit; Atlas, E.; Colomer, Ramon; Lupu, Ruth

doi:10.3892/ijo.24.3.591

Cited by 84 publications

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“…Cerulenin and C75 may promote HER2 to enter the nucleus and to induce transcriptional activation of HER2-targeted genes. Indeed, we have shown that cerulenin-and C75-induced FAS inhibition is accompanied by the accumulation, activation, and͞or cellular relocalization of multiple pro-and antiapoptotic proteins (17). Moreover, HER2-negative MDA-MB-231 cells engineered to overexpress HER2 became hypersensitive to chemical FAS inhibitors in the absence of FAS protein levels comparable to those found in SK-Br3 cells (see Fig.…”

Section: Discussionmentioning

confidence: 84%

“…Because no effect was observed on cancer cells expressing physiological levels of HER2, these results reveal that tumor-associated FAS hyperactivity specifically regulates p185 HER2 oncoprotein in HER2 overexpres- sors. We previously reported a positive correlation between high levels of FAS expression and the amplification and͞or overexpression of HER2 (17), whereas HER2 overexpression was recently found to up-regulate FAS in breast cancer cells (35). Therefore, it is reasonable to propose that a bidirectional cross-talk between FAS and HER2 is taking place in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Cell lines were obtained from the American Type Culture Collection, and they were routinely grown in improved MEM (Biosource International, Camarillo, CA) containing 5% FBS and 2 mM L-glutamine as described (16,17). MDA-MB-231͞ HER2 cells were constructed by transfection of MDA-MB-231 cells with pRC͞CMV containing the full-length HER2 cDNA, and then Abbreviations: FAS, fatty acid synthase; siRNA, small interfering RNA; RNAi, RNA interference; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling.…”

Section: Methodsmentioning

confidence: 99%

“…Concentration-effect curves were generated as a plot of the fraction of surviving cells versus drug concentration by using a colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction assay (16,17).…”

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confidence: 99%

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Inhibition of fatty acid synthase (FAS) suppressesHER2/neu(erbB-2) oncogene overexpression in cancer cells

Menendez

Vellón

Mehmi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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323

275

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Fatty acid synthase (FAS) activity is a potential therapeutic target to treat cancer and obesity. Here, we have identified a molecular link between FAS and HER2 (erbB-2) oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185 HER2 oncoprotein expression and tyrosinekinase activity in breast and ovarian HER2 overexpressors. Similarly, p185 HER2 expression was dramatically down-regulated when FAS gene expression was silenced by using the highly sequencespecific mechanism of RNA interference (RNAi). Pharmacological and RNAi-mediated silencing of FAS specifically down-regulated HER2 mRNA and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional repressor of HER2. A cytoplasmic redistribution of p185 HER2 was associated with marked morphological changes of FAS RNAi-transfected cells, whereas chemical inhibitors of FAS promoted a striking nuclear accumulation of p185 HER2 . The simultaneous targeting of FAS and HER2 by chemical FAS inhibitors and the humanized antibody directed against p185 HER2 trastuzumab, respectively, was synergistically cytotoxic toward HER2 overexpressors. Similarly, concurrent RNAi-mediated silencing of FAS and HER2 genes synergistically stimulated apoptotic cell death in HER2 overexpressors. p185 HER2 was synergistically down-regulated after simultaneous inhibition of FAS and HER2 by either pharmacological inhibitors or small interfering RNA. These findings provide evidence of an active role of FAS in cancer evolution by specifically regulating oncogenic proteins closely related to malignant transformation, strongly suggesting that HER2 oncogene may act as the key molecular sensor of energy imbalance after the perturbation of tumor-associated FAS hyperactivity in cancer cells.trastuzumab ͉ small interfereing RNA ͉ chemotherapy ͉ lipogenesis ͉ Herceptin T he biosynthetic enzyme fatty acid synthase (FAS) is the major enzyme required for the anabolic conversion of dietary carbohydrates to fatty acids, and it functions normally in cells with high lipid metabolism. Under normal physiological conditions, any FAS increase is tightly regulated by a number of environmental, hormonal, and nutritional signals (1, 2). However, human tissue studies have demonstrated that infiltrating carcinomas of the breast constitutively express high levels of FAS compared to nontransformed human epithelial tissue (3-8). Furthermore, increased levels of FAS accompany the development of in situ carcinoma of the breast, suggesting a potential link between increased expression and increased risk of breast cancer development (9). Remarkably, overexpression and hyperactivity of FAS is associated with more aggressive breast and ovarian cancers (3-8, 10). The early and nearly universal up-regulation of FAS in many human cancers and its association with poor clinical outcome both strengthen the hypothesis that FAS is involved in the development, maintenance, and enhancement of the malignant...

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of fatty acid synthase (FAS) suppressesHER2/neu(erbB-2) oncogene overexpression in cancer cells

Menendez

Vellón

Mehmi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

323

275

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“…Cell FAS activity assay FAS activity in cells was assessed as described previously with appropriate modifications (Menendez et al, 2004). After cells were harvested, pelleted by centrifugation, resuspended in cold assay buffer (100 mM potassium phosphate buffer, 1 mM EDTA, 0.6 mM PMSF and 1 mM dithiolthreitol, pH 7.0) ultrasonically disrupted and centrifuged at 12000 rpm for 30 min at 4 °C, the supernatant was collected for the overall reaction assay.…”

Section: Fas Inhibition Assaysmentioning

confidence: 99%

Inhibitory Effects of Onion (Allium cepa L.) Extract on Proliferation of Cancer Cells and Adipocytes via Inhibiting Fatty Acid Synthase

Wang¹,

Tian²,

Ma³

2012

Asian Pacific Journal of Cancer Prevention

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Onions (Allium cepa L.) are widely used in the food industry for its nutritional and aromatic properties. Our studies showed that ethyl acetate extract of onion (EEO) had potent inhibitory effects on animal fatty acid synthase (FAS), and could induce apoptosis in FAS over-expressing human breast cancer MDA-MB-231 cells. Furthermore, this apoptosis was accompanied by reduction of intracellular FAS activity and could be rescued by 25 mM or 50 mM exogenous palmitic acids, the final product of FAS catalyzed synthesis. These results suggest that the apoptosis induced by EEO occurs via inhibition of FAS. We also found that EEO could suppress lipid accumulation during the differentiation of 3T3-L1 adipocytes, which was also related to its inhibition of intracellular FAS activity. Since obesity is closely related to breast cancer and obese patients are at elevated risk of developing various cancers, these findings suggested that onion might be useful for preventing obesity-related malignancy.

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Inhibition of cell cycle and induction of apoptosis by 2-oxoheksyl isothiocyanate and alyssin in cell lines carrying various inheritedBRCA1 mutations

Misiewicz

Kozar²,

Skupińska

et al. 2005

Drug Dev. Res.

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An important aspect of the chemopreventive activity of isothiocyanates (ITC) is their ability to induce cell growth inhibition and apoptosis. In this study, the effect of two sulforaphane analogues, 2-oxoheksyl isothiocyanate and alyssin, on lymphoblastoid cells, derived from people carrying four different germ-line mutations in BRCA1 gene, was tested and compared to the effect on wild type cells. The mutations studied were: C61G; 3819del5; 4153delA, and 5382INSC. Changes in cell viability and density after 2-oxoheksyl isothiocyanate and alyssin treatment were evaluated, as well as cell cycle progression, mitochondrial membrane potential changes, and phosphatidylserine externalization. Both isothiocyanates were shown to reduce cell viability and density in all cell lines tested, as well as the change in cell cycle phase's distribution. The response of cells to two ITC tested was various, as well as mutation type-modulated. We found that change of cellular maintenance by chemopreventive agents can be modulated by single allele BRCA1 mutation. Drug Dev. Res. 65:84-92, 2005.

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Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-κB

Cited by 84 publications

References 0 publications

Inhibition of fatty acid synthase (FAS) suppressesHER2/neu(erbB-2) oncogene overexpression in cancer cells

Inhibition of fatty acid synthase (FAS) suppressesHER2/neu(erbB-2) oncogene overexpression in cancer cells

Inhibitory Effects of Onion (Allium cepa L.) Extract on Proliferation of Cancer Cells and Adipocytes via Inhibiting Fatty Acid Synthase

Inhibition of cell cycle and induction of apoptosis by 2-oxoheksyl isothiocyanate and alyssin in cell lines carrying various inheritedBRCA1 mutations

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