A Fatty Acid Synthase Blockade Induces Tumor Cell-cycle Arrest by Down-regulating Skp2

Knowles, Lynn M.; Axelrod, Fumiko; Browne, Cecille D.; Smith, Jeffrey W.

doi:10.1074/jbc.m405061200

Cited by 129 publications

(118 citation statements)

References 32 publications

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“…Further study of the factors correlated with the accumulation of lipid may lead to the identification of novel genes/pathways that have roles in lipid accumulation/sensing in vivo, possibly providing new targets for therapeutic treatment of obesity and other disorders. It should be noted that similar lipidsensing systems might be recapitulated in other cell types such as tumor cells, some of which are heavily dependent on lipids as a source of nutrient (Knowles et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis

et al. 2011

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SUMMARYObesity is characterized by an expansion of white adipose tissue mass that results from an increase in the size and the number of adipocytes. However, the mechanisms responsible for the formation of adipocytes during development and the molecular mechanisms regulating their increase and maintenance in adulthood are poorly understood. Here, we report the use of leptinluciferase BAC transgenic mice to track white adipose tissue (WAT) development and guide the isolation and molecular characterization of adipocytes during development using DNA microarrays. These data reveal distinct transcriptional programs that are regulated during murine WAT development in vivo. By using a de novo cis-regulatory motif discovery tool (FIRE), we identify two early gene clusters whose promoters show significant enrichment for NRF2/ETS transcription factor binding sites. We further demonstrate that Ets transcription factors, but not Nrf2, are regulated during early adipogenesis and that Ets2 is essential for the normal progression of the adipocyte differentiation program in vitro. These data identify ETS2 as a functionally important transcription factor in adipogenesis and its possible role in regulating adipose tissue mass in adults can now be tested. Our approach also provides the basis for elucidating the function of other gene networks during WAT development in vivo. Finally these data confirm that although gene expression during adipogenesis in vitro recapitulates many of the patterns of gene expression in vivo, there are additional developmental transitions in pre and post-natal adipose tissue that are not evident in cell culture systems.

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Section: Discussionmentioning

confidence: 98%

Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis

et al. 2011

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“…Cancer cells, however, synthesize more than 90% of their triacylglycerol de novo, requiring increased FASN expression ( 1 ). The important role of FASN in cancer cell proliferation/survival and its potential oncogenic function have been demonstrated in several previous studies (2)(3)(4)(5)(6)(7)(8).…”

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confidence: 91%

Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production

Liu

Dong

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org in normal nonadipose tissues/cells. Cancer cells, however, synthesize more than 90% of their triacylglycerol de novo, requiring increased FASN expression ( 1 ). The important role of FASN in cancer cell proliferation/survival and its potential oncogenic function have been demonstrated in several previous studies ( 2-8 ).Overexpression of FASN has been associated with poor prognosis and higher risk of recurrence of human cancers of the breast ( 9-12 ) and prostate ( 13 ), as well as many other types of cancers ( 1 ), suggesting that increased FASN expression may also contribute to disease progression and treatment failure. In particular, FASN overexpression has been found in a drug-selected breast cancer cell line, and this elevation contributes to cellular resistance to Adriamycin (doxorubicin) and mitoxantrone in breast ( 14 ) and to gemcitabine in pancreatic cancer cells ( 15 ). However, the mechanism by which FASN contributes to drug resistance is currently unknown.In this study, we investigated the molecular mechanism of FASN-mediated drug resistance using FASN overexpression stable clones of MCF7 cells and found that FASN overexpression causes resistance to multiple anticancer drugs as well as to ␥ -irradiation via inhibiting treatmentinduced ceramide production, caspase 8 activation, and apoptosis. Further studies showed that FASN overexpression suppresses tumor necrosis factor (TNF)-␣ production, nuclear factor (NF)-B activation, and drug-induced activation of neutral sphingomyelinase (nSMase). Hence, FASN overexpression may cause drug resistance by inhibiting TNF-␣ expression, which in turn suppresses activation of NF-B and nSMase and, thus, reduced ceramide production, caspase 8 activation, and apoptosis.Abstract Fatty acid synthase (FASN) is a key enzyme in the synthesis of palmitate, the precursor of major nutritional, energetic, and signaling lipids. FASN expression is upregulated in many human cancers and appears to be important for cancer cell survival. Overexpression of FASN has also been found to associate with poor prognosis and higher risk of recurrence of human cancers. Indeed, elevated FASN expression has been shown to contribute to drug resistance. However, the mechanism of FASN-mediated drug resistance is currently unknown. In this study, we show that FASN overexpression causes resistance to multiple anticancer drugs via inhibiting drug-induced ceramide production, caspase 8 activation, and apoptosis. We also show that FASN overexpression suppresses tumor necrosis factor-␣ production and nuclear factor-B activation as well as drug-induced activation of neutral sphingomyelinase. Thus, TNF-␣ may play an important role in mediating FASN function in drug resistance. Mammalian FASN is a homo-dimer of a multifunctional protein of ‫ف‬ 270 kDa containing seven catalytic domains: ␤ -ketoacyl synthase, malonyl/acetyltransferase, dehydrogenase, enoyl reductase, ␤ -ketoacyl reductase, acyl carrier protein, and thioesterase . Under normal physiologi...

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“…Orlistat negatively influences FASN activity and has a significant effect on the antitumor activity by inducing remarkable diversification such as a complete G2-M phase loss, S-phase accumulation and the 2 and XIA ZHAO emerging sub-G1 (apoptotic) cell increase, and repression of the promoter activity of Her2/neu gene (18). Ovarian cancer is the most common malignancy of the female reproductive tract and is the leading cause of death from gynecologic types of cancer; it is currently the fifth leading cause of female cancer-related mortality (19).…”

Section: Introductionmentioning

confidence: 99%

Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat

Huang

Tang

Zhou

et al. 2012

International Journal of Oncology

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Abstract.Orlistat is an orally administered anti-obesity drug that has shown significant antitumor activity in a variety of tumor cells. To identify the proteins involved in its antitumor activity, we employed a proteomic approach to reveal protein expression changes in the human ovarian cancer cell line SKOV3, following Orlistat treatment. Protein expression profiles were analyzed by 2-dimensional polyacrylamide gel electrophoresis (2-DE) and protein identification was performed on a MALDI-Q-TOF MS/MS instrument. More than 110 differentially expressed proteins were visualized by 2-DE and Coomassie brilliant blue staining. Furthermore, 71 proteins differentially expressed proteins were positively identified via mass spectrometry (MS)/MS analysis. In particular, PKM1/2, a key enzyme involved in tumorigenesis, was found to be significantly downregulated in SKOV3 cells following treatment with Orlistat. Moreover, PKM1/2 was proved to be downregulated in SKOV3 cells by western blot analysis after treatment with Orlistat. Taken together, using proteomic tools, we identified several differentially expressed proteins that underwent Orlistat-induced apoptosis, particularly PKM2. These changes confirmed our hypothesis that Orlistat is a potential inhibitor of ovarian cancer and can be used as a novel adjuvant antitumor agent. IntroductionIn the 1920s, the Nobel Prize winner Otto Warburg observed a marked increase in glycolysis and enhanced lactate production in tumor cells even when maintained in conditions of high oxygen tension (termed Warburg effect), leading to widespread concerns about the metabolic changes in human types of cancer (1). Either as a consequence or as a cause, alterations of cancer cell-intrinsic metabolism have been considered as essential hallmarks of cancer. Among these metabolic changes, de novo fatty acid biosynthesis was found elevated in the majority of human types of cancer, such as prostate (2), colorectal (3), ovarian (4), bladder (5), esophageal (6), gastric (7), lung (8), endometrial (9), breast (10) and soft tissue sarcomas (11). Fatty acid synthase (FASN) is regarded as a key regulator of de novo fatty acid synthesis and was widely found upregulated in a wide variety of human malignancies and their pre-neoplastic lesions. Recent studies also reveal that FASN is associated with the stage of cancer and indicate a poor prognosis (12). Thus, FASN could be considered as a reliable predictor of recurrence and disease-free survival along with neo-plastic stage (13). In vivo treatment with inhibitors of FASN has been proven to lead to markedly decreased survival in human cancer xenografts (14) and silencing of the FASN gene by siRNA also inhibits cancer cell growth and ultimately induces cancer cell apoptosis (15). Therefore, agents that inhibit FASN and the de novo fatty-acid synthesis pathways could be considered as novel antitumor strategies.Orlistat, an anti-obesity drug approved by the US Food and Drug Administration, which possesses extremely low oral bio-availability (16), exhibits anti-p...

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A Fatty Acid Synthase Blockade Induces Tumor Cell-cycle Arrest by Down-regulating Skp2

Cited by 129 publications

References 32 publications

Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis

Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis

Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production

Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat

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