Mammalian Neutral Sphingomyelinases: Regulation and Roles in Cell Signaling Responses

Wu, Bill X.; Clarke, Christopher J.; Hannun, Yusuf A.

doi:10.1007/s12017-010-8120-z

Cited by 132 publications

(114 citation statements)

References 88 publications

(131 reference statements)

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“…nSMase-2 isoform was chosen among the nSMase family because nSMase-2, but not nSMase-1 or nSMase-3, has been identifi ed as the major TNF-␣ -responsive nSMase in MCF7 cells ( 17,18 ).…”

Section: Transient Knockdown Of Target Genesmentioning

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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“…nSMase-2 isoform was chosen among the nSMase family because nSMase-2, but not nSMase-1 or nSMase-3, has been identifi ed as the major TNF-␣ -responsive nSMase in MCF7 cells ( 17,18 ).…”

Section: Transient Knockdown Of Target Genesmentioning

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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“…Although initially considered as inert structural molecules, sphingolipids are now recognized as important mediators for signal transduction pathways affecting various cell functions (Merrill et al, 1997;Milhas et al, 2010;Wu et al, 2010). Bone deformities in mouse models lacking a functional Smpd3 (sphingomyelin phosphodiesterase 3) gene underscore the importance of sphingolipid metabolism in skeletal tissues (Aubin et al, 2005;Stoffel et al, 2005).…”

Section: The Fro Mutation Abolishes Nsmase2 Activity But Does Not Affmentioning

confidence: 99%

“…nSMase2 cleaves sphingomyelin to generate the lipid second messenger ceramide (Merrill et al, 1997;Wu et al, 2010). Thus, a loss of functional nSMase2 could have dual effects, i.e., both a decrease in ceramide levels and an increase in sphingomyelin levels in tissues in which Smpd3 is normally expressed.…”

Section: Gene Expression Analysismentioning

confidence: 99%

A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization

Khavandgar¹,

Poirier²,

Clarke³

et al. 2011

J Exp Med

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“…It is mainly synthesized in the endoplasmic reticulum (ER) by ceramide synthases (CerSs), which attach a variety of fatty acid residues to long chain bases such as sphingosine and dihydrosphingosine, or by hydrolysis of sphingomyelin that is catalyzed by different sphingomyelinases (SMases) in distinct cellular compartments such as the plasma membrane, lysosomes, the Golgi apparatus, and mitochondria (10)(11)(12)(13)(14)(15). Increase of ceramide levels through upregulation of CerSs or SMases leads to induction of apoptosis and other cell signaling pathways critical for cell death, senescence, autophagy, or cell cycle arrest.…”

Section: Introductionmentioning

confidence: 99%

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

Kong

Zhu

Itokazu

et al. 2018

Journal of Lipid Research

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Mammalian Neutral Sphingomyelinases: Regulation and Roles in Cell Signaling Responses

Cited by 132 publications

References 88 publications

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

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

A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

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