Targeted Suppression and Knockout of ASCT2 or LAT1 in Epithelial and Mesenchymal Human Liver Cancer Cells Fail to Inhibit Growth
Amino acid transporters alanine-serine-cysteine transporter 2 (ASCT2) and L-Type Amino Acid Transporter 1 (LAT1) are coordinately enhanced in human cancers where among other roles, they are thought to drive mechanistic target-of-rapamycin (mTOR) growth signaling. To assess ASCT2 and LAT1 as therapeu...
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| description | Amino acid transporters alanine-serine-cysteine transporter 2 (ASCT2) and L-Type Amino Acid Transporter 1 (LAT1) are coordinately enhanced in human cancers where among other roles, they are thought to drive mechanistic target-of-rapamycin (mTOR) growth signaling. To assess ASCT2 and LAT1 as therapeutic targets, nine unique short hairpin RNA (shRNA) vectors were used to stably suppress transporter expression in human epithelial (Hep3B) and mesenchymal (SK-Hep1) hepatocellular carcinoma (HCC) cell lines. In addition, six unique CRISPR-Cas9 vectors were used to edit the ASCT2 (
) and LAT1 (
) genes in epithelial (HUH7) and mesenchymal (SK-Hep1) HCC cells. Both approaches successfully diminished glutamine (ASCT2) and leucine (LAT1) initial-rate transport proportional to transporter protein suppression. In spite of profoundly reduced glutamine or leucine transport (up to 90%), transporter suppression or knockout failed to substantially affect cellular proliferation or basal and amino acid-stimulated mTORC1 growth signaling in either HCC cell type. Only LAT1 knockout in HUH7 slightly reduced growth rate. However, intracellular accumulation of radiolabeled glutamine and leucine over longer time periods largely recovered to control levels in ASCT2 and LAT1 knockout cells, respectively, which partially explains the lack of an impaired growth phenotype. These data collectively establish that in an in vitro context, human epithelial and mesenchymal HCC cell lines adapt to ASCT2 or LAT1 knockout. These results comport with an emerging model of amino acid exchangers like ASCT2 and LAT1 as "harmonizers", not drivers, of amino acid accumulation and signaling, despite their long-established dominant role in initial-rate amino acid transport. |
| doi_str_mv | 10.3390/ijms19072093 |
| format | Article |
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) and LAT1 (
) genes in epithelial (HUH7) and mesenchymal (SK-Hep1) HCC cells. Both approaches successfully diminished glutamine (ASCT2) and leucine (LAT1) initial-rate transport proportional to transporter protein suppression. In spite of profoundly reduced glutamine or leucine transport (up to 90%), transporter suppression or knockout failed to substantially affect cellular proliferation or basal and amino acid-stimulated mTORC1 growth signaling in either HCC cell type. Only LAT1 knockout in HUH7 slightly reduced growth rate. However, intracellular accumulation of radiolabeled glutamine and leucine over longer time periods largely recovered to control levels in ASCT2 and LAT1 knockout cells, respectively, which partially explains the lack of an impaired growth phenotype. These data collectively establish that in an in vitro context, human epithelial and mesenchymal HCC cell lines adapt to ASCT2 or LAT1 knockout. These results comport with an emerging model of amino acid exchangers like ASCT2 and LAT1 as "harmonizers", not drivers, of amino acid accumulation and signaling, despite their long-established dominant role in initial-rate amino acid transport.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms19072093</identifier><identifier>PMID: 30029480</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Accumulation ; Alanine ; Amino Acid Transport System ASC - metabolism ; Amino acids ; Amino Acids - metabolism ; Biological Transport - drug effects ; Cell Death - drug effects ; Cell Proliferation - drug effects ; CRISPR ; CRISPR-Cas Systems - genetics ; Epithelium - pathology ; Expression vectors ; Gene expression ; Gene Knockout Techniques ; Glutamine ; Growth rate ; Hepatocellular carcinoma ; Hepatocytes ; Humans ; Large Neutral Amino Acid-Transporter 1 - metabolism ; Leucine ; Liver ; Liver cancer ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Mechanistic Target of Rapamycin Complex 1 - metabolism ; Mesenchyme ; Mesoderm - pathology ; Mifepristone - pharmacology ; Minor Histocompatibility Antigens - metabolism ; Phenotypes ; Protein transport ; Proteins ; Rapamycin ; RNA, Antisense - metabolism ; RNA, Small Interfering - metabolism ; Serine ; Signal Transduction - drug effects ; Sodium - metabolism ; Therapeutic applications ; TOR protein ; Tumor cell lines</subject><ispartof>International journal of molecular sciences, 2018-07, Vol.19 (7), p.2093</ispartof><rights>2018. This work is licensed under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 by the authors. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-1efe7f32bf8f4f05418b74827b492aa0a6986c076ff055aeb45c9920725709a03</citedby><cites>FETCH-LOGICAL-c412t-1efe7f32bf8f4f05418b74827b492aa0a6986c076ff055aeb45c9920725709a03</cites><orcidid>0000-0001-8482-0636</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073291/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073291/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30029480$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bothwell, Paige J</creatorcontrib><creatorcontrib>Kron, Clare D</creatorcontrib><creatorcontrib>Wittke, Evan F</creatorcontrib><creatorcontrib>Czerniak, Bradley N</creatorcontrib><creatorcontrib>Bode, Barrie P</creatorcontrib><title>Targeted Suppression and Knockout of ASCT2 or LAT1 in Epithelial and Mesenchymal Human Liver Cancer Cells Fail to Inhibit Growth</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Amino acid transporters alanine-serine-cysteine transporter 2 (ASCT2) and L-Type Amino Acid Transporter 1 (LAT1) are coordinately enhanced in human cancers where among other roles, they are thought to drive mechanistic target-of-rapamycin (mTOR) growth signaling. To assess ASCT2 and LAT1 as therapeutic targets, nine unique short hairpin RNA (shRNA) vectors were used to stably suppress transporter expression in human epithelial (Hep3B) and mesenchymal (SK-Hep1) hepatocellular carcinoma (HCC) cell lines. In addition, six unique CRISPR-Cas9 vectors were used to edit the ASCT2 (
) and LAT1 (
) genes in epithelial (HUH7) and mesenchymal (SK-Hep1) HCC cells. Both approaches successfully diminished glutamine (ASCT2) and leucine (LAT1) initial-rate transport proportional to transporter protein suppression. In spite of profoundly reduced glutamine or leucine transport (up to 90%), transporter suppression or knockout failed to substantially affect cellular proliferation or basal and amino acid-stimulated mTORC1 growth signaling in either HCC cell type. Only LAT1 knockout in HUH7 slightly reduced growth rate. However, intracellular accumulation of radiolabeled glutamine and leucine over longer time periods largely recovered to control levels in ASCT2 and LAT1 knockout cells, respectively, which partially explains the lack of an impaired growth phenotype. These data collectively establish that in an in vitro context, human epithelial and mesenchymal HCC cell lines adapt to ASCT2 or LAT1 knockout. These results comport with an emerging model of amino acid exchangers like ASCT2 and LAT1 as "harmonizers", not drivers, of amino acid accumulation and signaling, despite their long-established dominant role in initial-rate amino acid transport.</description><subject>Accumulation</subject><subject>Alanine</subject><subject>Amino Acid Transport System ASC - metabolism</subject><subject>Amino acids</subject><subject>Amino Acids - metabolism</subject><subject>Biological Transport - drug effects</subject><subject>Cell Death - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>CRISPR</subject><subject>CRISPR-Cas Systems - genetics</subject><subject>Epithelium - pathology</subject><subject>Expression vectors</subject><subject>Gene expression</subject><subject>Gene Knockout Techniques</subject><subject>Glutamine</subject><subject>Growth rate</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatocytes</subject><subject>Humans</subject><subject>Large Neutral Amino Acid-Transporter 1 - metabolism</subject><subject>Leucine</subject><subject>Liver</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Mechanistic Target of Rapamycin Complex 1 - metabolism</subject><subject>Mesenchyme</subject><subject>Mesoderm - pathology</subject><subject>Mifepristone - pharmacology</subject><subject>Minor Histocompatibility Antigens - metabolism</subject><subject>Phenotypes</subject><subject>Protein transport</subject><subject>Proteins</subject><subject>Rapamycin</subject><subject>RNA, Antisense - metabolism</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Serine</subject><subject>Signal Transduction - drug effects</subject><subject>Sodium - metabolism</subject><subject>Therapeutic applications</subject><subject>TOR protein</subject><subject>Tumor cell lines</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkUlvFDEQhS0EIgvcOCNLXDgwUF568QVpNMomBnHIcLbcHjvtodtubHdQbvz0eEiIBk5VVn16Vc8PoTcEPjIm4JPbjYkIaCgI9gwdE07pAqBunh_0R-gkpR0AZbQSL9ERK63gLRyj3xsVb0w2W3w9T1M0KbngsfJb_MUH_SPMGQeLl9erDcUh4vVyQ7Dz-GxyuTeDU8Mf9qtJxuv-bizvy3lUHq_drYl4pbzeFzMMCZ8rN-Ac8JXvXecyvojhV-5foRdWDcm8fqyn6Pv52WZ1uVh_u7haLdcLzQnNC2KsaSyjnW0tt1Bx0nYNb2nTcUGVAlWLttbQ1LYMK2U6XmkhaPmWqgGhgJ2izw-609yNZquNz1ENcopuVPFOBuXkvxPvenkTbmUNDaOCFIH3jwIx_JxNynJ0SRdnypswJ1l2McZaoPtd7_5Dd2GOvtiTlIDgFa0JLdSHB0rHkFI09ukYAnIfrTyMtuBvDw08wX-zZPccx57H</recordid><startdate>20180719</startdate><enddate>20180719</enddate><creator>Bothwell, Paige J</creator><creator>Kron, Clare D</creator><creator>Wittke, Evan F</creator><creator>Czerniak, Bradley N</creator><creator>Bode, Barrie P</creator><general>MDPI AG</general><general>MDPI</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8482-0636</orcidid></search><sort><creationdate>20180719</creationdate><title>Targeted Suppression and Knockout of ASCT2 or LAT1 in Epithelial and Mesenchymal Human Liver Cancer Cells Fail to Inhibit Growth</title><author>Bothwell, Paige J ; Kron, Clare D ; Wittke, Evan F ; Czerniak, Bradley N ; Bode, Barrie P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-1efe7f32bf8f4f05418b74827b492aa0a6986c076ff055aeb45c9920725709a03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Accumulation</topic><topic>Alanine</topic><topic>Amino Acid Transport System ASC - metabolism</topic><topic>Amino acids</topic><topic>Amino Acids - metabolism</topic><topic>Biological Transport - drug effects</topic><topic>Cell Death - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>CRISPR</topic><topic>CRISPR-Cas Systems - genetics</topic><topic>Epithelium - pathology</topic><topic>Expression vectors</topic><topic>Gene expression</topic><topic>Gene Knockout Techniques</topic><topic>Glutamine</topic><topic>Growth rate</topic><topic>Hepatocellular carcinoma</topic><topic>Hepatocytes</topic><topic>Humans</topic><topic>Large Neutral Amino Acid-Transporter 1 - metabolism</topic><topic>Leucine</topic><topic>Liver</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>Mechanistic Target of Rapamycin Complex 1 - metabolism</topic><topic>Mesenchyme</topic><topic>Mesoderm - pathology</topic><topic>Mifepristone - pharmacology</topic><topic>Minor Histocompatibility Antigens - metabolism</topic><topic>Phenotypes</topic><topic>Protein transport</topic><topic>Proteins</topic><topic>Rapamycin</topic><topic>RNA, Antisense - metabolism</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Serine</topic><topic>Signal Transduction - drug effects</topic><topic>Sodium - metabolism</topic><topic>Therapeutic applications</topic><topic>TOR protein</topic><topic>Tumor cell lines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bothwell, Paige J</creatorcontrib><creatorcontrib>Kron, Clare D</creatorcontrib><creatorcontrib>Wittke, Evan F</creatorcontrib><creatorcontrib>Czerniak, Bradley N</creatorcontrib><creatorcontrib>Bode, Barrie P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bothwell, Paige J</au><au>Kron, Clare D</au><au>Wittke, Evan F</au><au>Czerniak, Bradley N</au><au>Bode, Barrie P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeted Suppression and Knockout of ASCT2 or LAT1 in Epithelial and Mesenchymal Human Liver Cancer Cells Fail to Inhibit Growth</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2018-07-19</date><risdate>2018</risdate><volume>19</volume><issue>7</issue><spage>2093</spage><pages>2093-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Amino acid transporters alanine-serine-cysteine transporter 2 (ASCT2) and L-Type Amino Acid Transporter 1 (LAT1) are coordinately enhanced in human cancers where among other roles, they are thought to drive mechanistic target-of-rapamycin (mTOR) growth signaling. To assess ASCT2 and LAT1 as therapeutic targets, nine unique short hairpin RNA (shRNA) vectors were used to stably suppress transporter expression in human epithelial (Hep3B) and mesenchymal (SK-Hep1) hepatocellular carcinoma (HCC) cell lines. In addition, six unique CRISPR-Cas9 vectors were used to edit the ASCT2 (
) and LAT1 (
) genes in epithelial (HUH7) and mesenchymal (SK-Hep1) HCC cells. Both approaches successfully diminished glutamine (ASCT2) and leucine (LAT1) initial-rate transport proportional to transporter protein suppression. In spite of profoundly reduced glutamine or leucine transport (up to 90%), transporter suppression or knockout failed to substantially affect cellular proliferation or basal and amino acid-stimulated mTORC1 growth signaling in either HCC cell type. Only LAT1 knockout in HUH7 slightly reduced growth rate. However, intracellular accumulation of radiolabeled glutamine and leucine over longer time periods largely recovered to control levels in ASCT2 and LAT1 knockout cells, respectively, which partially explains the lack of an impaired growth phenotype. These data collectively establish that in an in vitro context, human epithelial and mesenchymal HCC cell lines adapt to ASCT2 or LAT1 knockout. These results comport with an emerging model of amino acid exchangers like ASCT2 and LAT1 as "harmonizers", not drivers, of amino acid accumulation and signaling, despite their long-established dominant role in initial-rate amino acid transport.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>30029480</pmid><doi>10.3390/ijms19072093</doi><orcidid>https://orcid.org/0000-0001-8482-0636</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of molecular sciences, 2018-07, Vol.19 (7), p.2093 |
| issn | 1422-0067 1661-6596 1422-0067 |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Accumulation Alanine Amino Acid Transport System ASC - metabolism Amino acids Amino Acids - metabolism Biological Transport - drug effects Cell Death - drug effects Cell Proliferation - drug effects CRISPR CRISPR-Cas Systems - genetics Epithelium - pathology Expression vectors Gene expression Gene Knockout Techniques Glutamine Growth rate Hepatocellular carcinoma Hepatocytes Humans Large Neutral Amino Acid-Transporter 1 - metabolism Leucine Liver Liver cancer Liver Neoplasms - metabolism Liver Neoplasms - pathology Mechanistic Target of Rapamycin Complex 1 - metabolism Mesenchyme Mesoderm - pathology Mifepristone - pharmacology Minor Histocompatibility Antigens - metabolism Phenotypes Protein transport Proteins Rapamycin RNA, Antisense - metabolism RNA, Small Interfering - metabolism Serine Signal Transduction - drug effects Sodium - metabolism Therapeutic applications TOR protein Tumor cell lines |
| title | Targeted Suppression and Knockout of ASCT2 or LAT1 in Epithelial and Mesenchymal Human Liver Cancer Cells Fail to Inhibit Growth |
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