Growth arrest and apoptosis induced by quercetin is not linked to adipogenic conversion of human preadipocytes

Morikawa, Keiko; Ikeda, Chiharu; Nonaka, Mitsuko; Suzuki, Itsuko S.

doi:10.1016/j.metabol.2007.07.008

Cited by 12 publications

(7 citation statements)

References 40 publications

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“…We report for the first time induction of BAD, a pro-apoptotic gene by 0.3 μM PEITC in mammary cells. A time-dependent upregulation of BAD, along with increase in apoptosis has been observed in pre-adipocyte cell line AML-I treated with 100 μmol/L quercetin, a dietary flavonoid (15). BAD belongs to the Bcl-2 family of proteins and regulates apoptosis (16, 17).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Effects of Phenethyl Isothiocyanate and Sulforaphane on Gene Expression in Breast Cancer and Normal Mammary Epithelial Cells

Telang

Brazeau

Morris

2009

Exp Biol Med (Maywood)

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Phenethyl isothiocyanate (PEITC) and sulforaphane (SF) exhibit tumor preventive activity in lung, prostate, breast and colon cancers. Our objective was to examine the effect of these two isothiocyanates on estrogen receptor-related genes, and genes related to apoptosis and cell cycle in the estrogen-dependent breast cancer cell line MCF7 and in normal human epithelial breast (HME) cells. We treated cells with 0.3 μM or 3.0 μM concentrations of PEITC or SF. In HME cells, gene expression was significantly altered for 23 genes by PEITC at a concentration of 0.3 μM and 4 genes at 3.0 μM. SF altered the expression of 16 genes at a concentration of 0.3 μM and 2 genes at 3.0 μM. In HME cells, genes altered by both PEITC and SF exhibited changes in gene expression that were similar in extent as well as direction of change. In MCF-7 cells, PEITC did not produce any significant changes in the gene expression at both treatment levels. SF produced significant changes in 7 genes, but only at the higher treatment level of 3.0 μM. Normal mammary cells exhibited more changes in the expression of estrogen receptor related genes than did breast cancer cells, and significantly these changes occurred predominantly at the low concentration of 0.3 μM, a concentration achievable by dietary input of isothiocyanates. Novel findings were the upregulation of the pro-apoptotic gene BAD and estrogen receptor beta gene in normal human mammary cells. These gene alterations observed, along with upregulation of tumor suppressors p21 and p27, may provide a protective effect to mammary cells against breast cancer.

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Section: Discussionmentioning

confidence: 99%

Comparison of the Effects of Phenethyl Isothiocyanate and Sulforaphane on Gene Expression in Breast Cancer and Normal Mammary Epithelial Cells

Telang

Brazeau

Morris

2009

Exp Biol Med (Maywood)

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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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“…Furthermore, over-expression of Mcl-1 protects cells from apoptosis induced by a variety of agents, including UV, etoposide, staurosporine, actinomycin D, and others (27–30). Two groups (4, 31) have indicated a decrease of Mcl-1 level in quercetin-treated cells.…”

Section: Introductionmentioning

confidence: 99%

Quercetin Induces Tumor-Selective Apoptosis through Downregulation of Mcl-1 and Activation of Bax

Cheng

Gao

Zhang

et al. 2010

Clinical Cancer Research

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Purpose: To investigate the in vivo antitumor efficacy of quercetin in U937 xenografts and the functional roles of Mcl-1 and Bax in quercetin-induced apoptosis in human leukemia.Experimental Design: Leukemia cells were treated with quercetin, after which apoptosis, Mcl-1 expression, and Bax activation and translocation were evaluated. The efficacy of quercetin as well as Mcl-1 expression and Bax activation were investigated in xenografts of U937 cells.Results: Administration of quercetin caused pronounced apoptosis in both transformed and primary leukemia cells but not in normal blood peripheral mononuclear cells. Quercetin-induced apoptosis was accompanied by Mcl-1 downregulation and Bax conformational change and mitochondrial translocation that triggered cytochrome c release. Knockdown of Bax by siRNA reversed quercetin-induced apoptosis and abrogated the activation of caspase and apoptosis. Ectopic expression of Mcl-1 attenuated quercetinmediated Bax activation, translocation, and cell death. Conversely, interruption of Mcl-1 by siRNA enhanced Bax activation and translocation, as well as lethality induced by quercetin. However, the absence of Bax had no effect on quercetin-mediated Mcl-1 downregulation. Furthermore, in vivo administration of quercetin attenuated tumor growth in U937 xenografts. The TUNEL-positive apoptotic cells in tumor sections increased in quercetin-treated mice as compared with controls. Mcl-1 downregulation and Bax activation were also observed in xenografts.Conclusions: These data suggest that quercetin may be useful for the treatment of leukemia by preferentially inducing apoptosis in leukemia versus normal hematopoietic cells through a process involving Mcl-1 downregulation, which, in turn, potentiates Bax activation and mitochondrial translocation, culminating in apoptosis. Clin Cancer Res; 16(23); 5679-91. Ó2010 AACR.

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Growth arrest and apoptosis induced by quercetin is not linked to adipogenic conversion of human preadipocytes

Cited by 12 publications

References 40 publications

Comparison of the Effects of Phenethyl Isothiocyanate and Sulforaphane on Gene Expression in Breast Cancer and Normal Mammary Epithelial Cells

Comparison of the Effects of Phenethyl Isothiocyanate and Sulforaphane on Gene Expression in Breast Cancer and Normal Mammary Epithelial Cells

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

Quercetin Induces Tumor-Selective Apoptosis through Downregulation of Mcl-1 and Activation of Bax

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