Growth arrest induced by C75, A fatty acid synthase inhibitor, Was partially modulated by p38 MAPK but not by p53 in human hepatocellular carcinoma

Gao, Y; Lin, Liping; Zhu, Cai-hua; Chen, Yi; Hou, Yongtai; Ding, Jian

doi:10.4161/cbt.5.8.2883

Cited by 46 publications

(38 citation statements)

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“…Seventy-two hours after transfection of cells with siRNA, 1 ACi of 55 mCi/mmol [2][3][4][5][6][7][8][9][10][11][12][13][14] C]acetic acid (GE Healthcare) was added per six wells for 2 h. Cells were washed with PBS, scraped into 2% KOH, and incubated overnight at 80jC to saponify lipids. Sterols were extracted by adding hexanes and spinning for 5 min at 600 Â g. The organic phase containing sterols was discarded.…”

Section: Methodsmentioning

confidence: 99%

Control of Cell Growth and Survival by Enzymes of the Fatty Acid Synthesis Pathway in HCT-116 Colon Cancer Cells

Zhan

Ginanni

Tota

et al. 2008

Clinical Cancer Research

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Purpose: For many tumor cells, de novo lipogenesis is a requirement for growth and survival.A considerable body of work suggests that inhibition of this pathway may be a powerful approach to antineoplastic therapy. It has recently been shown that inhibition of various steps in the lipogenic pathway individually can induce apoptosis or loss of viability in tumor cells. However, it is not clear whether quantitative differences exist in the ability of lipogenic enzymes to control tumor cell survival. We present a systematic approach that allows for a direct comparison of the control of lipogenic pathway enzymes over tumor cell growth and apoptosis using different cancer cells. Experimental Design: RNA interference-mediated, graded down-regulation of fatty acid synthase (FAS) pathway enzymes was employed in combination with measurements of lipogenesis, apoptosis, and cell growth. Results: In applying RNA interference titrations to two lipogenic enzymes, acetyl-CoA carboxylase 1 (ACC1) and FAS, we show that ACC1and FAS both significantly control cell growth and apoptosis in HCT-116 cells. These results also extend to PC-3 and A2780 cancer cells. Conclusions: Control of tumor cell survival by different steps in de novo lipogenesis can be quantified. Because ACC1 and FAS both significantly control tumor cell growth and apoptosis, we propose that pharmacologic inhibitors of either enzyme might be useful agents in targeting cancer cells that critically rely on fatty acid synthesis. The experimental approach described here may be extended to other targets or disease-relevant pathways to identify steps suitable for therapeutic intervention.

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Section: Methodsmentioning

confidence: 99%

Control of Cell Growth and Survival by Enzymes of the Fatty Acid Synthesis Pathway in HCT-116 Colon Cancer Cells

Zhan

Ginanni

Tota

et al. 2008

Clinical Cancer Research

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“…31,33,36 Specifically, silencing of FASN using siRNA or inhibition of FASN activity via the small molecule C75 led to decreased HCC cell proliferation and increased apoptosis. Mechanistically, it has been suggested that FASN may regulate the AKT 33 and p38MAPK 36 cascades. However, overexpression of FASN in the liver, either alone or in combination with other putative oncogenes, such as activated N-Ras or c-Met, does not trigger tumor formation in mice.…”

Section: Increased Lipogenesis In Hccmentioning

confidence: 99%

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

et al. 2017

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Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is an aggressive cancer type with limited treatment options. Cumulating evidence underlines a crucial role of aberrant lipid biosynthesis (a process known as de novo lipogenesis) along carcinogenesis. Previous studies showed that suppression of fatty acid synthase (FASN), the major enzyme responsible for de novo lipogenesis, is highly detrimental for the in vitro growth of HCC cell lines. To assess whether de novo lipogenesis is required for liver carcinogenesis, we have generated various mouse models of liver cancer by stably overexpressing candidate oncogenes in the mouse liver via hydrodynamic gene delivery. We found that overexpression of FASN in the mouse liver is unable to malignantly transform hepatocytes. However, genetic deletion of FASN totally suppresses hepatocarcinogenesis driven by AKT and AKT/c-Met protooncogenes in mice. On the other hand, liver tumor development is completely unaffected by FASN depletion in mice coexpressing b-catenin and c-Met. Our data indicate that tumors might be either addicted to or independent from de novo lipogenesis for their growth depending on the oncogenes involved. Additional investigation is required to unravel the molecular mechanisms whereby some oncogenes render cancer cells resistant to inhibition of de novo lipogenesis.

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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).…”

mentioning

confidence: 99%

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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Growth arrest induced by C75, A fatty acid synthase inhibitor, Was partially modulated by p38 MAPK but not by p53 in human hepatocellular carcinoma

Cited by 46 publications

References 0 publications

Control of Cell Growth and Survival by Enzymes of the Fatty Acid Synthesis Pathway in HCT-116 Colon Cancer Cells

Control of Cell Growth and Survival by Enzymes of the Fatty Acid Synthesis Pathway in HCT-116 Colon Cancer Cells

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

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

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