Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activity and expression of fatty acid synthase (FAS), a critical enzyme in the de novo biosynthesis of fatty acids in mammals, is exquisitely sensitive to nutritional regulation of lipogenesis in liver or adipose tissue. Surprisingly, a number of studies have demonstrated hyperactivity and overexpression of FAS (oncogenic antigen-519) in a biologically aggressive subset of human breast carcinomas, suggesting that FAS-dependent neoplastic lipogenesis is unresponsive to nutritional regulation. We have assessed the role of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) on the enzymatic activity and protein expression of tumor-associated FAS in SK-Br3 human breast cancer cells, an experimental paradigm of FAS-overexpressing tumor cells in which FAS enzyme constitutes up to 28%, by weight, of the cytosolic proteins. Of the omega-3 PUFAs tested, alpha-linolenic acid (ALA) dramatically reduced FAS activity in a dose-dependent manner (up to 61%). omega-3 PUFA docosahexaenoic acid (DHA) demonstrated less marked but still significant inhibitory effects on FAS activity (up to 37%), whereas eicosapentaenoic acid (EPA) was not effective. Of the omega-6 fatty acids tested, gamma-linolenic acid (GLA) was the most effective dose-dependent inhibitor of FAS activity, with a greater than 75% FAS activity reduction. Remarkably, omega-6 PUFAs linoleic acid (LA) and arachidonic acid (ARA), suppressors of both hepatic and adipocytic FAS-dependent lipogenesis, had no significant inhibitory effects on the activity of tumor-associated FAS in SK-Br3 breast cancer cells. Western blotting studies showed that down-regulation of FAS protein expression tightly correlated with previously observed inhibition of FAS activity, suggesting that ALA-, DHA-, and GLA-induced changes in FAS activity resulted from effects at the protein level. We investigated whether the FAS inhibitory effect of GLA and omega-3 PUFAs correlated with a cytotoxic effect related to a peroxidative mechanism. Measurement of cell viability by MTT assay indicated a significant cellular toxicity after ALA and GLA exposures. Furthermore, we observed a significant correlation between the ability of PUFAs to repress FAS and cause cell toxicity. In the presence of anti-oxidants (vitamin E), ALA and GLA dramatically lost their ability to inhibit FAS activity. Interestingly, a combination of ALA and GLA was FAS inhibitory in an additive manner, and this FAS repression was only partially reversible by vitamin E. In examining the molecular mechanisms underlying resistance of breast cancer-associated FAS to normal dietary fatty acid-induced suppression, a dramatic decrease of FAS accumulation was found after exposure of SK-Br3 cells to mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (MAPK ERK1/2) inhibitor U0126, phosphatidylinositol-3'-kinase (PI-3'K) blocker LY294002, and/or anti-HER-2/neu antibody trastuzumab. Interestingly, a long-term exposure to pharmacological inhibitors of FAS activity cerulenin [(2S,3R) 2,3-epoxy-4-oxo-7E,10E-dodecadienamide] or C75 also resulted in a significant reduction of FAS accumulation. These data indicate that: a) GLA- and omega-3 PUFA-induced repression of tumor-associated FAS may result, at least in part, from a non-specific cytotoxic effect due to peroxidative mechanisms; b) alternatively, GLA and omega-3 PUFAs have a suppressive effect on FAS expression and activity that can result in the accumulation of toxic fluxes of the FAS substrate malonyl-CoA; c) GLA- and/or omega-3 PUFA-induced repression of tumor-associated FAS may represent a novel mechanism of PUFA-induced cytotoxicity clinically useful against breast carcinomas carrying overexpression of FAS enzyme; d) fundamental differences in the ability of FAS gene to respond to normal fatty acid's regulatory actions in lipogenic tissues may account for the observed extremely high levels of FAS in breast carcinoma; and e) FAS overexpression in SK-Br3 breast cancer cells is driven by increases in HER-2/neu signaling, acting in major part through a constitutive downstream art through a constitutive downstream activation of the MAPK ERK1/2 and PI-3'K/AKT transduction cascades.
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PMID:Overexpression and hyperactivity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive to normal arachidonic fatty acid-induced suppression in lipogenic tissues but it is selectively inhibited by tumoricidal alpha-linolenic and gamma-linolenic fatty acids: a novel mechanism by which dietary fat can alter mammary tumorigenesis. 1513 77

Trastuzumab (Herceptin) is a humanized antibody directed against the extracellular domain of the tyrosine kinase orphan receptor Her-2/neu (erbB-2) that has shown therapeutic efficacy against Her-2/neu-overexpressing breast tumors. However, less than 35% of patients with Her-2/neu-overexpressing metastatic breast cancer respond to trastuzumab as a single agent, whereas the remaining cases do not demonstrate tumor regression. Furthermore, the majority of patients who achieve an initial response generally acquire resistance within one year. Therefore, the identification of the potential mechanisms of resistance to trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with trastuzumab. Recent studies in breast cancer cells have revealed a bi-directional connection between Her-2/neu and fatty acid synthase (FAS), a major lipogenic enzyme catalyzing the synthesis of long-chain saturated fatty acids from the 2-carbon donors malonyl-CoA and acetyl-CoA. Her-2/neu overexpression stimulates the FAS promoter and ultimately mediates increased endogenous fatty synthesis, and this Her-2/neu-mediated induction of breast cancer-associated FAS is inhibitable by trastuzumab. On the other hand, chemical FAS inhibitors as well as RNA interference-mediated silencing of FAS gene repress Her-2/neu gene expression at the transcriptional level. Moreover, specific FAS blockade synergistically sensitizes breast cancer cells carrying Her-2/neu-oncogene amplification and/or overexpression to trastuzumab-induced cell growth inhibition and apoptotic cell death. Strikingly, FAS inhibition synergistically interacts with trastuzumab in Her-2/neu-negative breast cancer cells engineered to overexpress Her-2/neu, thus suggesting that the molecular linkage between FAS activity and functioning of Her-2/neu cannot be explained only on the basis of a transcriptional repression of Her-2/neu gene promoter. Interestingly, while in liver and adipose tissue FAS produces fat from excess carbon consumed as carbohydrates, which is ultimately stored as triglycerides, in epithelial cancer cells, FAS activity is mainly involved in the production of phospholipids partitioning into detergent-resistant membrane microdomains (lipid raft-aggregates), which point to an active role of FAS in the deregulation of membrane functioning in tumor cells. Importantly, clusters of Her-2/neu and EGFR (erbB-1) co-localize with lipid rafts and the lipid environment in the cell membrane of breast cancer cells profoundly influences their association properties and biological functions. We hypothesize that pharmacological or small interference RNA-induced inhibition of breast cancer-associated FAS will result in major changes in the synthesis of phospholipids which, in turn, should impair a correct cellular localization of Her-2/neu at the cellular membrane of breast cancer cells. In this working model, FAS inhibition could induce a shift in the equilibrium between transport of Her-2/neu to and from the membrane favoring an increased Her-2/neu internalization followed by intracellular degradation, thus enhancing the mechanism of action of the anti-Her-2/neu antibody trastuzumab. Moreover, the inhibition of FAS-driven lipid rafts will also negatively affect EGFR-Her-2/neu cross-talk, an important mechanism of trastuzumab resistance. In summary, the specific blockade of a novel molecular linkage between FAS-regulated membrane composition and functioning of transmembrane growth factor receptors EGFR and Her-2/neu may represent a previously unrecognized therapeutic approach circumventing trastuzumab resistance in breast carcinomas.
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PMID:Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells. 1578 Apr 99

The expression and activity of Fatty Acid Synthase (FASN; the sole enzyme capable of the reductive de novo synthesis of long-chain fatty acids from acetyl-CoA, malonyl-CoA, and nicotinamide adenine dinucleotide phosphate -NADPH-) is extremely low in nearly all nonmalignant adult tissues, whereas it is significantly up-regulated or activated in many cancer types, thus creating the potential for a large therapeutic index. Since the pioneering observation that inhibition of FASN activity by the mycotoxin cerulenin preferentially kills cancer cells and retards the growth of tumors in xenografts models, numerous in vitro and in vivo studies have confirmed the potential of FASN as a target for antineoplastic intervention. Other FASN inhibitors such as the cerulenin derivative C75, the beta-lactone orlistat, the green tea polyphenol epigallocatechin-3-gallate (EGCG) and other naturally occurring flavonoids (i.e., luteolin, quercetin, and kaempferol), as well as the antibiotic triclosan, have been identified and have been shown to limit cancer cell growth by inducing apoptotic cell death. Though the exact mode of action of these FASN inhibitors is under discussion, it has been revealed that depletion of end-product fatty acids, toxic intracellular accumulation of supra-physiological concentrations of the FASN substrate malonyl-CoA and/or limited membrane synthesis and/or functioning by altered production of phospholipids partitioning into detergent-resistant membrane microdomains (lipid raft-aggregates), can explain, at least in part, the cytostatic, cytotoxic as well as the apoptotic effects occurring upon pharmacological inhibition of FASN activity in cancer cells. Moreover, several cancer-associated molecular features including nonfunctioning p53, overexpression of the Her-2/neu (erbB-2) oncogene, and hyperactivation of the PI-3'K down-stream effector protein kinase B (AKT), appear to determine an exacerbated sensitivity to FASN inhibition-induced cancer cell death. Although few of these inhibitors are expected to be "exclusively" selective for FASN, the potential of FASN as a target for antineoplastic intervention has eventually been confirmed by RNA interference (RNAi)-knockdown of FASN. Certainly, future studies should definitely elucidate the ultimate biochemical link between FASN inhibition and cancer cell death. Although the combination of FASN structural complexity and until recently the lack of X-ray crystallography data of mammalian FASN created a significant challenge in the exploitation of FASN as a valuable target for drug development, it is hoped that the improvement in the selectivity and potency of forthcoming novel FASN-targeted small molecule inhibitors by taking advantage, for instance, of the recent 4.5 A resolution X-ray crystallographic map of mammalian FASN, will direct the foundation of a new family of chemotherapeutic agents in cancer history.
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PMID:Pharmacological inhibitors of Fatty Acid Synthase (FASN)--catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents? 1716 65

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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PMID:Mediterranean dietary traditions for the molecular treatment of human cancer: anti-oncogenic actions of the main olive oil's monounsaturated fatty acid oleic acid (18:1n-9). 1716 66