BCH, an Inhibitor of System L Amino Acid Transporters, Induces Apoptosis in Cancer Cells
Purpose: L-Type amino acid transporter 1 (LAT1) is highly expressed in cancer cells to support their continuous growth and proliferation. We have examined the effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), an inhibitor of system L amino acid transporters, and the mechanism by whic...
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| Veröffentlicht in: | Biological & Pharmaceutical Bulletin 2008/06/01, Vol.31(6), pp.1096-1100 |
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| creator | Kim, Chun Sung Cho, Seon-Ho Chun, Hong Sung Lee, Sook-Young Endou, Hitoshi Kanai, Yoshikatsu Kim, Do Kyung |
| description | Purpose: L-Type amino acid transporter 1 (LAT1) is highly expressed in cancer cells to support their continuous growth and proliferation. We have examined the effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), an inhibitor of system L amino acid transporters, and the mechanism by which BCH suppresses cell growth in cancer cells. Methods: The effect of BCH and the mechanism of BCH on cell growth suppression in cancer cells were examined using amino acid transport measurement, MTT assay, DNA fragmentation analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunoblotting. Results: BCH inhibited L-leucine transport in a concentration-dependent manner, and it inhibited cell growth in a time-dependent manner in KB human oral epidermoid carcinoma cells, Saos2 human osteogenic sarcoma cells and C6 rat glioma cells. The formation of a DNA ladder was observed, and the number of TUNEL-positive cells was increased with BCH treatment. Furthermore, the proteolytic processing of caspase-3 in KB and C6 cells and of caspase-7 in KB, Saos2 and C6 cells was increased by BCH treatment. Conclusion: These results suggest that the inhibition of LAT1 activity by BCH leads to apoptotic cancer cell death by inducing intracellular depletion of neutral amino acids necessary for cancer cell growth. |
| doi_str_mv | 10.1248/bpb.31.1096 |
| format | Article |
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We have examined the effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), an inhibitor of system L amino acid transporters, and the mechanism by which BCH suppresses cell growth in cancer cells. Methods: The effect of BCH and the mechanism of BCH on cell growth suppression in cancer cells were examined using amino acid transport measurement, MTT assay, DNA fragmentation analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunoblotting. Results: BCH inhibited L-leucine transport in a concentration-dependent manner, and it inhibited cell growth in a time-dependent manner in KB human oral epidermoid carcinoma cells, Saos2 human osteogenic sarcoma cells and C6 rat glioma cells. The formation of a DNA ladder was observed, and the number of TUNEL-positive cells was increased with BCH treatment. Furthermore, the proteolytic processing of caspase-3 in KB and C6 cells and of caspase-7 in KB, Saos2 and C6 cells was increased by BCH treatment. Conclusion: These results suggest that the inhibition of LAT1 activity by BCH leads to apoptotic cancer cell death by inducing intracellular depletion of neutral amino acids necessary for cancer cell growth.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.31.1096</identifier><identifier>PMID: 18520037</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid ; Actins - biosynthesis ; Actins - genetics ; Amino Acid Transport Systems - antagonists & inhibitors ; Amino Acids, Cyclic - pharmacology ; anti-cancer therapy ; Antineoplastic Agents ; apoptosis ; Apoptosis - drug effects ; Blotting, Western ; cancer cell ; Caspases - metabolism ; Cell Division - drug effects ; Cell Line, Tumor ; DNA Fragmentation ; Enzyme Activation - drug effects ; Humans ; In Situ Nick-End Labeling ; KB Cells ; L-type amino acid transporter ; Large Neutral Amino Acid-Transporter 1 - genetics ; Large Neutral Amino Acid-Transporter 1 - metabolism ; Leucine - metabolism ; Tetrazolium Salts ; Thiazoles</subject><ispartof>Biological and Pharmaceutical Bulletin, 2008/06/01, Vol.31(6), pp.1096-1100</ispartof><rights>2008 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c688t-a48eaa79662a7b9b7ddd06a2e9321724ebdecaea097d98e474fe095dac215ed53</citedby><cites>FETCH-LOGICAL-c688t-a48eaa79662a7b9b7ddd06a2e9321724ebdecaea097d98e474fe095dac215ed53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,1884,27928,27929</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18520037$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Chun Sung</creatorcontrib><creatorcontrib>Cho, Seon-Ho</creatorcontrib><creatorcontrib>Chun, Hong Sung</creatorcontrib><creatorcontrib>Lee, Sook-Young</creatorcontrib><creatorcontrib>Endou, Hitoshi</creatorcontrib><creatorcontrib>Kanai, Yoshikatsu</creatorcontrib><creatorcontrib>Kim, Do Kyung</creatorcontrib><creatorcontrib>cResearch Center for Proteineous Materials Chosun University</creatorcontrib><creatorcontrib>eDepartment of Pharmacology Osaka University Graduate School of Medicine</creatorcontrib><creatorcontrib>aDepartment of Oral Physiology and The Second Stage of BK Chosun University College of Dentistry</creatorcontrib><creatorcontrib>dDepartment of Pharmacology and Toxicology Kyorin University School of Medicine</creatorcontrib><creatorcontrib>bDepartment of Biotechnology (BK Program Chosun University</creatorcontrib><title>BCH, an Inhibitor of System L Amino Acid Transporters, Induces Apoptosis in Cancer Cells</title><title>Biological & Pharmaceutical Bulletin</title><addtitle>Biol Pharm Bull</addtitle><description>Purpose: L-Type amino acid transporter 1 (LAT1) is highly expressed in cancer cells to support their continuous growth and proliferation. We have examined the effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), an inhibitor of system L amino acid transporters, and the mechanism by which BCH suppresses cell growth in cancer cells. Methods: The effect of BCH and the mechanism of BCH on cell growth suppression in cancer cells were examined using amino acid transport measurement, MTT assay, DNA fragmentation analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunoblotting. Results: BCH inhibited L-leucine transport in a concentration-dependent manner, and it inhibited cell growth in a time-dependent manner in KB human oral epidermoid carcinoma cells, Saos2 human osteogenic sarcoma cells and C6 rat glioma cells. The formation of a DNA ladder was observed, and the number of TUNEL-positive cells was increased with BCH treatment. Furthermore, the proteolytic processing of caspase-3 in KB and C6 cells and of caspase-7 in KB, Saos2 and C6 cells was increased by BCH treatment. Conclusion: These results suggest that the inhibition of LAT1 activity by BCH leads to apoptotic cancer cell death by inducing intracellular depletion of neutral amino acids necessary for cancer cell growth.</description><subject>2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid</subject><subject>Actins - biosynthesis</subject><subject>Actins - genetics</subject><subject>Amino Acid Transport Systems - antagonists & inhibitors</subject><subject>Amino Acids, Cyclic - pharmacology</subject><subject>anti-cancer therapy</subject><subject>Antineoplastic Agents</subject><subject>apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Blotting, Western</subject><subject>cancer cell</subject><subject>Caspases - metabolism</subject><subject>Cell Division - drug effects</subject><subject>Cell Line, Tumor</subject><subject>DNA Fragmentation</subject><subject>Enzyme Activation - drug effects</subject><subject>Humans</subject><subject>In Situ Nick-End Labeling</subject><subject>KB Cells</subject><subject>L-type amino acid transporter</subject><subject>Large Neutral Amino Acid-Transporter 1 - genetics</subject><subject>Large Neutral Amino Acid-Transporter 1 - metabolism</subject><subject>Leucine - metabolism</subject><subject>Tetrazolium Salts</subject><subject>Thiazoles</subject><issn>0918-6158</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkM1v1DAQxS0EosvCiTuyhMSF7mInjj9uLBGllVbiQJG4WY49S71K7GAnh_73eJstlbjYh_nNe28eQm8p2dKKyU_d2G1ruqVE8WdoRWsmNk1Fm-doRRSVG04beYFe5XwkhAhS1S_RBZVNRUgtVujXl_b6EpuAb8Kd7_wUE44H_OM-TzDgPd4NPkS8s97h22RCHmOaIOXLgrvZQsa7MY5TzD5jH3BrgoWEW-j7_Bq9OJg-w5vzv0Y_r77etteb_fdvN-1uv7FcymljmARjhOK8MqJTnXDOEW4qUHVFRcWgc2ANGKKEUxKYYAcgqnHGlhPBNfUafVh0xxT_zJAnPfhsSwITIM5ZC8qLUjl7jd7_Bx7jnELJpiljquZKypPcx4WyKeac4KDH5AeT7jUl-lS3LnXrmupT3YV-d9acuwHcE3vutwBXC1Cm3po-ht4HeHK2WXQ-9lEXXOqyQgnX5GRV5DWlhLCK0YdcnxehY57Mb_jnZNLkbQ-PqfjyPGw_juydSRpC_RcSkaao</recordid><startdate>20080601</startdate><enddate>20080601</enddate><creator>Kim, Chun Sung</creator><creator>Cho, Seon-Ho</creator><creator>Chun, Hong Sung</creator><creator>Lee, Sook-Young</creator><creator>Endou, Hitoshi</creator><creator>Kanai, Yoshikatsu</creator><creator>Kim, Do Kyung</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</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><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20080601</creationdate><title>BCH, an Inhibitor of System L Amino Acid Transporters, Induces Apoptosis in Cancer Cells</title><author>Kim, Chun Sung ; Cho, Seon-Ho ; Chun, Hong Sung ; Lee, Sook-Young ; Endou, Hitoshi ; Kanai, Yoshikatsu ; Kim, Do Kyung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c688t-a48eaa79662a7b9b7ddd06a2e9321724ebdecaea097d98e474fe095dac215ed53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid</topic><topic>Actins - biosynthesis</topic><topic>Actins - genetics</topic><topic>Amino Acid Transport Systems - antagonists & inhibitors</topic><topic>Amino Acids, Cyclic - pharmacology</topic><topic>anti-cancer therapy</topic><topic>Antineoplastic Agents</topic><topic>apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Blotting, Western</topic><topic>cancer cell</topic><topic>Caspases - metabolism</topic><topic>Cell Division - drug effects</topic><topic>Cell Line, Tumor</topic><topic>DNA Fragmentation</topic><topic>Enzyme Activation - drug effects</topic><topic>Humans</topic><topic>In Situ Nick-End Labeling</topic><topic>KB Cells</topic><topic>L-type amino acid transporter</topic><topic>Large Neutral Amino Acid-Transporter 1 - genetics</topic><topic>Large Neutral Amino Acid-Transporter 1 - metabolism</topic><topic>Leucine - metabolism</topic><topic>Tetrazolium Salts</topic><topic>Thiazoles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Chun Sung</creatorcontrib><creatorcontrib>Cho, Seon-Ho</creatorcontrib><creatorcontrib>Chun, Hong Sung</creatorcontrib><creatorcontrib>Lee, Sook-Young</creatorcontrib><creatorcontrib>Endou, Hitoshi</creatorcontrib><creatorcontrib>Kanai, Yoshikatsu</creatorcontrib><creatorcontrib>Kim, Do Kyung</creatorcontrib><creatorcontrib>cResearch Center for Proteineous Materials Chosun University</creatorcontrib><creatorcontrib>eDepartment of Pharmacology Osaka University Graduate School of Medicine</creatorcontrib><creatorcontrib>aDepartment of Oral Physiology and The Second Stage of BK Chosun University College of Dentistry</creatorcontrib><creatorcontrib>dDepartment of Pharmacology and Toxicology Kyorin University School of Medicine</creatorcontrib><creatorcontrib>bDepartment of Biotechnology (BK Program Chosun University</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biological & Pharmaceutical Bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Chun Sung</au><au>Cho, Seon-Ho</au><au>Chun, Hong Sung</au><au>Lee, Sook-Young</au><au>Endou, Hitoshi</au><au>Kanai, Yoshikatsu</au><au>Kim, Do Kyung</au><aucorp>cResearch Center for Proteineous Materials Chosun University</aucorp><aucorp>eDepartment of Pharmacology Osaka University Graduate School of Medicine</aucorp><aucorp>aDepartment of Oral Physiology and The Second Stage of BK Chosun University College of Dentistry</aucorp><aucorp>dDepartment of Pharmacology and Toxicology Kyorin University School of Medicine</aucorp><aucorp>bDepartment of Biotechnology (BK Program Chosun University</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BCH, an Inhibitor of System L Amino Acid Transporters, Induces Apoptosis in Cancer Cells</atitle><jtitle>Biological & Pharmaceutical Bulletin</jtitle><addtitle>Biol Pharm Bull</addtitle><date>2008-06-01</date><risdate>2008</risdate><volume>31</volume><issue>6</issue><spage>1096</spage><epage>1100</epage><pages>1096-1100</pages><issn>0918-6158</issn><eissn>1347-5215</eissn><abstract>Purpose: L-Type amino acid transporter 1 (LAT1) is highly expressed in cancer cells to support their continuous growth and proliferation. We have examined the effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), an inhibitor of system L amino acid transporters, and the mechanism by which BCH suppresses cell growth in cancer cells. Methods: The effect of BCH and the mechanism of BCH on cell growth suppression in cancer cells were examined using amino acid transport measurement, MTT assay, DNA fragmentation analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunoblotting. Results: BCH inhibited L-leucine transport in a concentration-dependent manner, and it inhibited cell growth in a time-dependent manner in KB human oral epidermoid carcinoma cells, Saos2 human osteogenic sarcoma cells and C6 rat glioma cells. The formation of a DNA ladder was observed, and the number of TUNEL-positive cells was increased with BCH treatment. Furthermore, the proteolytic processing of caspase-3 in KB and C6 cells and of caspase-7 in KB, Saos2 and C6 cells was increased by BCH treatment. Conclusion: These results suggest that the inhibition of LAT1 activity by BCH leads to apoptotic cancer cell death by inducing intracellular depletion of neutral amino acids necessary for cancer cell growth.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>18520037</pmid><doi>10.1248/bpb.31.1096</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid Actins - biosynthesis Actins - genetics Amino Acid Transport Systems - antagonists & inhibitors Amino Acids, Cyclic - pharmacology anti-cancer therapy Antineoplastic Agents apoptosis Apoptosis - drug effects Blotting, Western cancer cell Caspases - metabolism Cell Division - drug effects Cell Line, Tumor DNA Fragmentation Enzyme Activation - drug effects Humans In Situ Nick-End Labeling KB Cells L-type amino acid transporter Large Neutral Amino Acid-Transporter 1 - genetics Large Neutral Amino Acid-Transporter 1 - metabolism Leucine - metabolism Tetrazolium Salts Thiazoles |
| title | BCH, an Inhibitor of System L Amino Acid Transporters, Induces Apoptosis in Cancer Cells |
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