Fatty Acid Synthase Inhibition in Human Breast Cancer Cells Leads to Malonyl-CoA-Induced Inhibition of Fatty Acid Oxidation and Cytotoxicity
Inhibition of fatty acid synthase (FAS) induces apoptosis in human breast cancer cells in vitro and in vivo without toxicity to proliferating normal cells. We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apo...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2001-07, Vol.285 (2), p.217-223 |
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| creator | Thupari, Jagan N. Pinn, Michael L. Kuhajda, Francis P. |
| description | Inhibition of fatty acid synthase (FAS) induces apoptosis in human breast cancer cells in vitro and in vivo without toxicity to proliferating normal cells. We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apoptosis. In this study we further investigated the role of malonyl-CoA during FAS inhibition. We have found that: [i] inhibition of FAS with cerulenin causes carnitine palmitoyltransferase-1 (CPT-1) inhibition and fatty acid oxidation inhibition in MCF-7 human breast cancer cells likely mediated by elevation of malonyl-CoA; [ii] cerulenin cytotoxicity is due to the nonphysiological state of increased malonyl-CoA, decreased fatty acid oxidation, and decreased fatty acid synthesis; and [iii] the cytotoxic effect of cerulenin can be mimicked by simultaneous inhibition of CPT-1, with etomoxir, and fatty acid synthesis with TOFA, an acetyl-CoA carboxylase (ACC) inhibitor. This study identifies CPT-1 and ACC as two new potential targets for cancer chemotherapy. |
| doi_str_mv | 10.1006/bbrc.2001.5146 |
| format | Article |
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We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apoptosis. In this study we further investigated the role of malonyl-CoA during FAS inhibition. We have found that: [i] inhibition of FAS with cerulenin causes carnitine palmitoyltransferase-1 (CPT-1) inhibition and fatty acid oxidation inhibition in MCF-7 human breast cancer cells likely mediated by elevation of malonyl-CoA; [ii] cerulenin cytotoxicity is due to the nonphysiological state of increased malonyl-CoA, decreased fatty acid oxidation, and decreased fatty acid synthesis; and [iii] the cytotoxic effect of cerulenin can be mimicked by simultaneous inhibition of CPT-1, with etomoxir, and fatty acid synthesis with TOFA, an acetyl-CoA carboxylase (ACC) inhibitor. This study identifies CPT-1 and ACC as two new potential targets for cancer chemotherapy.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1006/bbrc.2001.5146</identifier><identifier>PMID: 11444828</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>acetyl-CoA carboxylase ; Acetyl-CoA Carboxylase - antagonists & inhibitors ; Apoptosis - drug effects ; Apoptosis - physiology ; Breast Neoplasms ; cancer ; Carnitine O-Palmitoyltransferase - antagonists & inhibitors ; carnitine palmitoyltransferase-1 ; Cell Survival - drug effects ; cerulenin ; Cerulenin - toxicity ; Enzyme Inhibitors - pharmacology ; Epoxy Compounds - pharmacology ; etomoxir ; fatty acid synthase ; Fatty Acid Synthases - antagonists & inhibitors ; Fatty Acids - metabolism ; Female ; Furans - pharmacology ; Humans ; Hypolipidemic Agents - pharmacology ; Kinetics ; Malonyl Coenzyme A - metabolism ; Malonyl Coenzyme A - toxicity ; malonyl-CoA ; Models, Biological ; Oxidation-Reduction ; Tumor Cells, Cultured</subject><ispartof>Biochemical and biophysical research communications, 2001-07, Vol.285 (2), p.217-223</ispartof><rights>2001 Academic Press</rights><rights>Copyright 2001 Academic Press.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-f6101d13c65dd52ea477b69a42112365ee6bd13f75158b6adafecab6817a4c0a3</citedby><cites>FETCH-LOGICAL-c406t-f6101d13c65dd52ea477b69a42112365ee6bd13f75158b6adafecab6817a4c0a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0006291X01951460$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11444828$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thupari, Jagan N.</creatorcontrib><creatorcontrib>Pinn, Michael L.</creatorcontrib><creatorcontrib>Kuhajda, Francis P.</creatorcontrib><title>Fatty Acid Synthase Inhibition in Human Breast Cancer Cells Leads to Malonyl-CoA-Induced Inhibition of Fatty Acid Oxidation and Cytotoxicity</title><title>Biochemical and biophysical research communications</title><addtitle>Biochem Biophys Res Commun</addtitle><description>Inhibition of fatty acid synthase (FAS) induces apoptosis in human breast cancer cells in vitro and in vivo without toxicity to proliferating normal cells. We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apoptosis. In this study we further investigated the role of malonyl-CoA during FAS inhibition. We have found that: [i] inhibition of FAS with cerulenin causes carnitine palmitoyltransferase-1 (CPT-1) inhibition and fatty acid oxidation inhibition in MCF-7 human breast cancer cells likely mediated by elevation of malonyl-CoA; [ii] cerulenin cytotoxicity is due to the nonphysiological state of increased malonyl-CoA, decreased fatty acid oxidation, and decreased fatty acid synthesis; and [iii] the cytotoxic effect of cerulenin can be mimicked by simultaneous inhibition of CPT-1, with etomoxir, and fatty acid synthesis with TOFA, an acetyl-CoA carboxylase (ACC) inhibitor. This study identifies CPT-1 and ACC as two new potential targets for cancer chemotherapy.</description><subject>acetyl-CoA carboxylase</subject><subject>Acetyl-CoA Carboxylase - antagonists & inhibitors</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - physiology</subject><subject>Breast Neoplasms</subject><subject>cancer</subject><subject>Carnitine O-Palmitoyltransferase - antagonists & inhibitors</subject><subject>carnitine palmitoyltransferase-1</subject><subject>Cell Survival - drug effects</subject><subject>cerulenin</subject><subject>Cerulenin - toxicity</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epoxy Compounds - pharmacology</subject><subject>etomoxir</subject><subject>fatty acid synthase</subject><subject>Fatty Acid Synthases - antagonists & inhibitors</subject><subject>Fatty Acids - metabolism</subject><subject>Female</subject><subject>Furans - pharmacology</subject><subject>Humans</subject><subject>Hypolipidemic Agents - pharmacology</subject><subject>Kinetics</subject><subject>Malonyl Coenzyme A - metabolism</subject><subject>Malonyl Coenzyme A - toxicity</subject><subject>malonyl-CoA</subject><subject>Models, Biological</subject><subject>Oxidation-Reduction</subject><subject>Tumor Cells, Cultured</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMFOAjEQhhujEUSvHk1fYLFddstyxI0ICYaDmnjbzLazoWZpSVuM-w4-tEVI5OJpkplv_pl8hNxyNuSMifu6dnKYMsaHOc_EGelzNmFJyll2TvosEkk64e89cuX9R6QiM7kkvVizrEiLPvmeQQgdnUqt6Etnwho80oVZ61oHbQ3Vhs53GzD0wSH4QEswEh0tsW09XSIoT4Olz9Ba07VJaafJwqidRHUaYht6cmb1pRX89sEoWnbBBvulpQ7dNblooPV4c6wD8jZ7fC3nyXL1tCiny0RmTISkEZxxxUdS5ErlKUI2HtdiAlnKeToSOaKo47gZ5zwvagEKGpRQi4KPIZMMRgMyPORKZ7132FRbpzfguoqzaq-12mut9lqrvda4cHdY2O7qDao__OgxAsUBwPj2p0ZXeakxqlLaoQyVsvq_7B81t4gp</recordid><startdate>20010713</startdate><enddate>20010713</enddate><creator>Thupari, Jagan N.</creator><creator>Pinn, Michael L.</creator><creator>Kuhajda, Francis P.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20010713</creationdate><title>Fatty Acid Synthase Inhibition in Human Breast Cancer Cells Leads to Malonyl-CoA-Induced Inhibition of Fatty Acid Oxidation and Cytotoxicity</title><author>Thupari, Jagan N. ; Pinn, Michael L. ; Kuhajda, Francis P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-f6101d13c65dd52ea477b69a42112365ee6bd13f75158b6adafecab6817a4c0a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>acetyl-CoA carboxylase</topic><topic>Acetyl-CoA Carboxylase - antagonists & inhibitors</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - physiology</topic><topic>Breast Neoplasms</topic><topic>cancer</topic><topic>Carnitine O-Palmitoyltransferase - antagonists & inhibitors</topic><topic>carnitine palmitoyltransferase-1</topic><topic>Cell Survival - drug effects</topic><topic>cerulenin</topic><topic>Cerulenin - toxicity</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Epoxy Compounds - pharmacology</topic><topic>etomoxir</topic><topic>fatty acid synthase</topic><topic>Fatty Acid Synthases - antagonists & inhibitors</topic><topic>Fatty Acids - metabolism</topic><topic>Female</topic><topic>Furans - pharmacology</topic><topic>Humans</topic><topic>Hypolipidemic Agents - pharmacology</topic><topic>Kinetics</topic><topic>Malonyl Coenzyme A - metabolism</topic><topic>Malonyl Coenzyme A - toxicity</topic><topic>malonyl-CoA</topic><topic>Models, Biological</topic><topic>Oxidation-Reduction</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thupari, Jagan N.</creatorcontrib><creatorcontrib>Pinn, Michael L.</creatorcontrib><creatorcontrib>Kuhajda, Francis P.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thupari, Jagan N.</au><au>Pinn, Michael L.</au><au>Kuhajda, Francis P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fatty Acid Synthase Inhibition in Human Breast Cancer Cells Leads to Malonyl-CoA-Induced Inhibition of Fatty Acid Oxidation and Cytotoxicity</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>2001-07-13</date><risdate>2001</risdate><volume>285</volume><issue>2</issue><spage>217</spage><epage>223</epage><pages>217-223</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><abstract>Inhibition of fatty acid synthase (FAS) induces apoptosis in human breast cancer cells in vitro and in vivo without toxicity to proliferating normal cells. We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apoptosis. In this study we further investigated the role of malonyl-CoA during FAS inhibition. We have found that: [i] inhibition of FAS with cerulenin causes carnitine palmitoyltransferase-1 (CPT-1) inhibition and fatty acid oxidation inhibition in MCF-7 human breast cancer cells likely mediated by elevation of malonyl-CoA; [ii] cerulenin cytotoxicity is due to the nonphysiological state of increased malonyl-CoA, decreased fatty acid oxidation, and decreased fatty acid synthesis; and [iii] the cytotoxic effect of cerulenin can be mimicked by simultaneous inhibition of CPT-1, with etomoxir, and fatty acid synthesis with TOFA, an acetyl-CoA carboxylase (ACC) inhibitor. This study identifies CPT-1 and ACC as two new potential targets for cancer chemotherapy.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>11444828</pmid><doi>10.1006/bbrc.2001.5146</doi><tpages>7</tpages></addata></record> |
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| subjects | acetyl-CoA carboxylase Acetyl-CoA Carboxylase - antagonists & inhibitors Apoptosis - drug effects Apoptosis - physiology Breast Neoplasms cancer Carnitine O-Palmitoyltransferase - antagonists & inhibitors carnitine palmitoyltransferase-1 Cell Survival - drug effects cerulenin Cerulenin - toxicity Enzyme Inhibitors - pharmacology Epoxy Compounds - pharmacology etomoxir fatty acid synthase Fatty Acid Synthases - antagonists & inhibitors Fatty Acids - metabolism Female Furans - pharmacology Humans Hypolipidemic Agents - pharmacology Kinetics Malonyl Coenzyme A - metabolism Malonyl Coenzyme A - toxicity malonyl-CoA Models, Biological Oxidation-Reduction Tumor Cells, Cultured |
| title | Fatty Acid Synthase Inhibition in Human Breast Cancer Cells Leads to Malonyl-CoA-Induced Inhibition of Fatty Acid Oxidation and Cytotoxicity |
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