Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Zecchin, Karina G.; Rossato, Franco Aparecido; Raposo, Helena Fonseca; Melo, Daniela R.; Alberici, Luciane C.; Oliveira, Helena Coutinho Franco de; Castilho, Roger F.; Coletta, Ricardo D.; Vercesi, Anı́bal E.; Graner, Edgard

doi:10.1038/labinvest.2010.157

Cited by 64 publications

(77 citation statements)

References 47 publications

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“…FASN inhibition has also been described as a sensitizer for cisplatin treatment in mice xenografted with human ovarian cancer cells (30). In fact, FASN is highly expressed across a wide range of human tumor types where its inhibition either induces apoptosis and/or synergizes with cytotoxic agents (31)(32)(33)(34)(35)(36)(37)(38). Consistent with these data, we show that inhibition of FASN with short hairpin RNAs also sensitized our CDH1-deficient cells to cisplatin treatment.…”

Section: Discussionsupporting

confidence: 87%

Proteomics of Genetically Engineered Mouse Mammary Tumors Identifies Fatty Acid Metabolism Members as Potential Predictive Markers for Cisplatin Resistance

Warmoes

Jaspers

et al. 2013

Molecular & Cellular Proteomics

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In contrast to various signatures that predict the prognosis of breast cancer patients, markers that predict chemotherapy response are still elusive. To detect such predictive biomarkers, we investigated early changes in protein expression using two mouse models for distinct breast cancer subtypes who have a differential knock-out status for the breast cancer 1, early onset ( Breast cancer is a heterogeneous disease consisting of a variety of subtypes that need different treatment strategies. In contrast to several prognostic signatures for clinical outcome, markers that predict treatment efficacy have been difficult to define. Reasons to explain this failure have been discussed elsewhere (1). A shortcoming of previous attempts to identify such markers may be that tumors were usually not challenged by drugs when sampled for analysis, or treatment was given a few weeks before sampling (neoadjuvant trials). Moreover, most previous studies focused on the analysis of gene expression to identify useful markers. However, differential expression of relevant factors, such as those involved in the DNA damage response, may be easier to detect shortly after chemotherapy-induced stress, and protein level readouts may provide a more direct way of assessing drug response.In this study, we aimed at detecting predictive biomarkers at the protein level by comparing the short term treatment response of platinum-sensitive versus platinum-resistant mouse mammary tumors that represent different breast cancer subtypes. As a sensitive model, we used the K14cre; Brca1 F/F ;p53 F/F mouse model (2) for BRCA1 1 -deficient breast cancer. The Brca1 Ϫ/Ϫ ;p53 Ϫ/Ϫ tumors that arise in this model include a large intragenic deletion of Brca1, and we have previously shown that these tumors are highly sensitive to cisplatin treatment (3). The response that we observed in this mouse model is consistent with the sensitivity of BRCA1-like breast cancer to intensive platinum-based chemotherapy in the clinic (4). Moreover, it was recently shown that triplenegative breast cancer patients frequently respond to cisplatin treatment, especially in patients with lower BRCA1 expression (5).As resistant model, we chose WAPcre;Cdh1 F/F ;p53

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Section: Discussionsupporting

confidence: 87%

Proteomics of Genetically Engineered Mouse Mammary Tumors Identifies Fatty Acid Metabolism Members as Potential Predictive Markers for Cisplatin Resistance

Warmoes

Jaspers

et al. 2013

Molecular & Cellular Proteomics

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“…Because both FAS and Akt are often overexpressed in breast cancers (Esslimani-Sahla et al, 2007;Vazquez-Martin et al, 2008;Wu et al, 2008), this indicates that this combination may have clinical utility in these cases. It has previously been shown that the inhibition of FAS and Akt can lead to apoptosis in breast cancer, as well as other types of cancer (Coticchia et al, 2009;Zecchin et al, 2011). In contrast, cells overexpressing FAS and Akt exhibit resistance to apoptosis (Liu et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…FAS is overexpressed in a variety of tumors and plays a key role in the migration and invasion of cancer cells. A number of reports have shown that anticancer agents induce apoptosis, in part, by blocking the activation of FAS and Akt pathways (Wrede et al, 2002;Coticchia et al, 2009;Zecchin et al, 2011). Akt prevents cells from undergoing apoptosis by inhibiting proapoptotic factors (Coticchia et al, 2009;Srinivasan et al, 2009).…”

Section: Combination Treatment With Lowered Doses Of Ho-3867 and Dox mentioning

confidence: 99%

Amelioration of Doxorubicin-Induced Cardiotoxicity by an Anticancer-Antioxidant Dual-Function Compound, HO-3867

Dayton¹,

Selvendiran²,

Meduru³

et al. 2011

J Pharmacol Exp Ther

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Doxorubicin (DOX) is a drug commonly used for the treatment of cancer. The development of resistance to DOX is common, and high cumulative doses cause potentially lethal cardiac side effects. HO-3867 (3,5-bis(4-fluorobenzylidene)-1-[(2,2,5,5-tetramethyl-2,5-dihydro-1-hydroxy-pyrrol-3-yl)methyl]piperidin-4-one), a synthetic curcumin analog, has been shown to exhibit both anticancer and cardioprotective effects. However, its cardioprotection in the setting of a conventional cancer therapy has not been established. This work investigated the use of HO-3867 and DOX to achieve a complementary outcome, i.e., increased toxicity toward cancer cells, and reduced cardiac toxicity. Combination treatment was investigated using DOXresistant MCF-7 breast cancer cells [MCF-7 multidrug-resistant (MDR)] and BALB/c mice. Lower doses of HO-3867 and DOX (5 and 2.5 M, respectively) reduced viability of MCF-7 MDR cells to an extent significantly greater than that when either drug was used alone, an effect equivalent to that induced by exposure to 50 M DOX. In normal cardiac cells, the loss of viability from combination treatment was significantly lower than that induced by 50 M DOX. Increases in apoptotic markers, e.g., cleaved caspase-3, and decreases in fatty acid synthase and pAkt expressions were observed by Western blotting. Mice treated with both HO-3867 and DOX showed significant improvement in cardiac functional parameters compared with mice treated with DOX alone. Reduced expression of Bcl-2 and pAkt was observed in mice treated with DOX alone, whereas mice given combination treatment showed levels similar to control. The study indicates that combination treatment of HO-3867 and DOX is a viable option for treatment of cancer with reduced cardiotoxic side effects.

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“…FASN is expressed at high levels in a variety of human tumors (11)(12)(13)(14), but exists at low levels in normal tissues. Various studies have reported that the inhibition of FASN expression suppresses cancer cell proliferation in vitro and in vivo (15)(16)(17)(18)(19)(20). Thus, FASN is considered a novel promising target for anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

microRNA-195 suppresses osteosarcoma cell invasion and migration in vitro by targeting FASN

et al. 2012

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Abstract. microRNAs are involved in different cancer-related processes. miR-195, one of the miR-16/15/195/424/497 family members, has been shown to act as a tumor suppressor during tumorigenesis. However, the function of miR-195 in osteosarcoma is still unclear. In our study, the miR-195 expression level was upregulated in osteosarcoma cells, by transfection with miR-195, and the fatty acid synthase (FASN) mRNA and protein expression levels were measured by RT-PCR and western blotting. Cell migration and invasion was measured using wound healing migration and Transwell invasion assays. We found that the upregulation of miR-195 greatly decreased cell invasion and the migration of U2OS. We also identified that FASN may be a direct target of miR-195 by the luciferase activity assay. These findings provide evidence that miR-195 plays a key role in inhibiting osteosarcoma cell migration and invasion through targeting FASN, and strongly suggest that exogenous miR-195 may have therapeutic value in treating osteosarcoma.

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Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Cited by 64 publications

References 47 publications

Proteomics of Genetically Engineered Mouse Mammary Tumors Identifies Fatty Acid Metabolism Members as Potential Predictive Markers for Cisplatin Resistance

Proteomics of Genetically Engineered Mouse Mammary Tumors Identifies Fatty Acid Metabolism Members as Potential Predictive Markers for Cisplatin Resistance

Amelioration of Doxorubicin-Induced Cardiotoxicity by an Anticancer-Antioxidant Dual-Function Compound, HO-3867

microRNA-195 suppresses osteosarcoma cell invasion and migration in vitro by targeting FASN

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