Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1
Abstract Background Tumor metastasis is a finely-tuned pathological process coupled to metabolic reprogramming that includes both glutamine and glucose. The solute carrier SLC38A3, a member of amino acid/polyamine/organocation (APC) superfamily, is an l -glutamine transporter. It is not clear whethe...
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| Veröffentlicht in: | Cancer letters 2017-05, Vol.393, p.8-15 |
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| creator | Wang, Yanhui Fu, Li Cui, Minqing Wang, Yongbin Xu, Yan Li, Molin Mi, Jun |
| description | Abstract Background Tumor metastasis is a finely-tuned pathological process coupled to metabolic reprogramming that includes both glutamine and glucose. The solute carrier SLC38A3, a member of amino acid/polyamine/organocation (APC) superfamily, is an l -glutamine transporter. It is not clear whether SLC38A3 involves the metastasis of NSCLC (non small cell lung cancer). Methods The scratch test and transwell assay were used to determine the ability of NSCLC to migrate. Cellular amino acids content was determined by mass spectrometry. The cellular response to glutamine/histidine deficiency was evaluated in A549 cells. The expression of SLC38A3 was assayed in clinical NSCLC and paratumor tissues by histoimmunochemistry staining. A nude mouse model of NSCLC metastasis was developed by tail vein injection of tumor cells. Results SLC38A3 was upregulated in metastatic NSCLC cells and its expression was correlated with prognosis of NSCLC patients. SLC38A3 overexpression promoted epithelial – mesenchymal transition (EMT) and migration of HCC827 and A549 human lung adenocarcinoma cells, and accelerated tumor metastasis in mice. We found that SLC38A3 decreased the cellular concentrations of glutamine and histidine, and the deficiency of glutamine or histidine activated PDK1/AKT signaling that in turn, triggered NSCLC metastasis. Conclusions SLC38A3 activated PDK1/AKT signaling and promoted metastasis of NSCLC through regulating glutamine and histidine transport, suggesting SLC38A3 as a potential therapeutic target for treatment of NSCLC. |
| doi_str_mv | 10.1016/j.canlet.2017.01.036 |
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| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1881751712</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>1_s2_0_S0304383517300782</els_id><sourcerecordid>4320990313</sourcerecordid><originalsourceid>FETCH-LOGICAL-c590t-cc32e34b5d08426df3776b362e356a282b1c5626dbaf1d6a69d6468966def5e3</originalsourceid><addsrcrecordid>eNqNUk2LFDEQDaK44-o_EAl48dJtJel89EUYZnUVBxR27yGdTkvG7s6YpBfm35tmVhf2ohASqHr18qpeIfSaQE2AiPeH2pp5dLmmQGQNpAYmnqANUZJWslXwFG2AQVMxxfgFepHSAQB4I_lzdEEVBco43SC_nfwcsLG-xzmaOR1DzC7im_2OqS3DxximkF3Ck8smleMTDgOew1ylyYwjtq5c4zL_wEWOLZVrIOHuVDizvzPZl9T3q6_kJXo2mDG5V_fvJbr99PF297naf7v-stvuK8tbyJW1jDrWdLwH1VDRD0xK0TFRglyYIrwjlouS6MxAemFE24tGqFaI3g3csUv07kxblP9aXMp68mnVZGYXlqSJUkRyIgn9D6hooQXWtgX69hH0EJY4lz4KSirFqZSkoJozysaQUnSDPkY_mXjSBPRqmj7os2l6NU0D0cW0UvbmnnzpJtf_LfrjUgF8OANcmdudd1En612Zdu-js1n3wf_rh8cEdvSzt2b86U4uPfSiE9Wgb9bFWfeGSAYgFWW_AV39vNg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1878852771</pqid></control><display><type>article</type><title>Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Wang, Yanhui ; Fu, Li ; Cui, Minqing ; Wang, Yongbin ; Xu, Yan ; Li, Molin ; Mi, Jun</creator><creatorcontrib>Wang, Yanhui ; Fu, Li ; Cui, Minqing ; Wang, Yongbin ; Xu, Yan ; Li, Molin ; Mi, Jun</creatorcontrib><description>Abstract Background Tumor metastasis is a finely-tuned pathological process coupled to metabolic reprogramming that includes both glutamine and glucose. The solute carrier SLC38A3, a member of amino acid/polyamine/organocation (APC) superfamily, is an l -glutamine transporter. It is not clear whether SLC38A3 involves the metastasis of NSCLC (non small cell lung cancer). Methods The scratch test and transwell assay were used to determine the ability of NSCLC to migrate. Cellular amino acids content was determined by mass spectrometry. The cellular response to glutamine/histidine deficiency was evaluated in A549 cells. The expression of SLC38A3 was assayed in clinical NSCLC and paratumor tissues by histoimmunochemistry staining. A nude mouse model of NSCLC metastasis was developed by tail vein injection of tumor cells. Results SLC38A3 was upregulated in metastatic NSCLC cells and its expression was correlated with prognosis of NSCLC patients. SLC38A3 overexpression promoted epithelial – mesenchymal transition (EMT) and migration of HCC827 and A549 human lung adenocarcinoma cells, and accelerated tumor metastasis in mice. We found that SLC38A3 decreased the cellular concentrations of glutamine and histidine, and the deficiency of glutamine or histidine activated PDK1/AKT signaling that in turn, triggered NSCLC metastasis. Conclusions SLC38A3 activated PDK1/AKT signaling and promoted metastasis of NSCLC through regulating glutamine and histidine transport, suggesting SLC38A3 as a potential therapeutic target for treatment of NSCLC.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2017.01.036</identifier><identifier>PMID: 28202352</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>3-Phosphoinositide-Dependent Protein Kinases - genetics ; 3-Phosphoinositide-Dependent Protein Kinases - metabolism ; A549 Cells ; Adenocarcinoma - enzymology ; Adenocarcinoma - genetics ; Adenocarcinoma - pathology ; Adenocarcinoma of Lung ; Amino acids ; Animals ; Carcinoma, Non-Small-Cell Lung - enzymology ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - secondary ; Cell Movement ; Conflicts of interest ; Enzyme Activation ; Epithelial-Mesenchymal Transition ; Glutamic Acid - deficiency ; Glutamine ; Grants ; Hematology, Oncology and Palliative Medicine ; Histidine - deficiency ; Humans ; Lung cancer ; Lung Neoplasms - enzymology ; Lung Neoplasms - genetics ; Lung Neoplasms - pathology ; Medical prognosis ; Metabolism ; Metabolites ; Metastasis ; Mice, Inbred BALB C ; Mice, Nude ; NSCLC ; PDK1 ; Phosphorylation ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Pulmonary arteries ; Real time ; Signal Transduction ; SLC38A3 ; Sodium-Calcium Exchanger - genetics ; Sodium-Calcium Exchanger - metabolism ; Transfection</subject><ispartof>Cancer letters, 2017-05, Vol.393, p.8-15</ispartof><rights>Elsevier B.V.</rights><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><rights>Copyright Elsevier Limited May 1, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c590t-cc32e34b5d08426df3776b362e356a282b1c5626dbaf1d6a69d6468966def5e3</citedby><cites>FETCH-LOGICAL-c590t-cc32e34b5d08426df3776b362e356a282b1c5626dbaf1d6a69d6468966def5e3</cites><orcidid>0000-0001-5788-3965</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.canlet.2017.01.036$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,45974</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28202352$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Yanhui</creatorcontrib><creatorcontrib>Fu, Li</creatorcontrib><creatorcontrib>Cui, Minqing</creatorcontrib><creatorcontrib>Wang, Yongbin</creatorcontrib><creatorcontrib>Xu, Yan</creatorcontrib><creatorcontrib>Li, Molin</creatorcontrib><creatorcontrib>Mi, Jun</creatorcontrib><title>Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>Abstract Background Tumor metastasis is a finely-tuned pathological process coupled to metabolic reprogramming that includes both glutamine and glucose. The solute carrier SLC38A3, a member of amino acid/polyamine/organocation (APC) superfamily, is an l -glutamine transporter. It is not clear whether SLC38A3 involves the metastasis of NSCLC (non small cell lung cancer). Methods The scratch test and transwell assay were used to determine the ability of NSCLC to migrate. Cellular amino acids content was determined by mass spectrometry. The cellular response to glutamine/histidine deficiency was evaluated in A549 cells. The expression of SLC38A3 was assayed in clinical NSCLC and paratumor tissues by histoimmunochemistry staining. A nude mouse model of NSCLC metastasis was developed by tail vein injection of tumor cells. Results SLC38A3 was upregulated in metastatic NSCLC cells and its expression was correlated with prognosis of NSCLC patients. SLC38A3 overexpression promoted epithelial – mesenchymal transition (EMT) and migration of HCC827 and A549 human lung adenocarcinoma cells, and accelerated tumor metastasis in mice. We found that SLC38A3 decreased the cellular concentrations of glutamine and histidine, and the deficiency of glutamine or histidine activated PDK1/AKT signaling that in turn, triggered NSCLC metastasis. Conclusions SLC38A3 activated PDK1/AKT signaling and promoted metastasis of NSCLC through regulating glutamine and histidine transport, suggesting SLC38A3 as a potential therapeutic target for treatment of NSCLC.</description><subject>3-Phosphoinositide-Dependent Protein Kinases - genetics</subject><subject>3-Phosphoinositide-Dependent Protein Kinases - metabolism</subject><subject>A549 Cells</subject><subject>Adenocarcinoma - enzymology</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - pathology</subject><subject>Adenocarcinoma of Lung</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Carcinoma, Non-Small-Cell Lung - enzymology</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - secondary</subject><subject>Cell Movement</subject><subject>Conflicts of interest</subject><subject>Enzyme Activation</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Glutamic Acid - deficiency</subject><subject>Glutamine</subject><subject>Grants</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Histidine - deficiency</subject><subject>Humans</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - enzymology</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - pathology</subject><subject>Medical prognosis</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Metastasis</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>NSCLC</subject><subject>PDK1</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Pulmonary arteries</subject><subject>Real time</subject><subject>Signal Transduction</subject><subject>SLC38A3</subject><subject>Sodium-Calcium Exchanger - genetics</subject><subject>Sodium-Calcium Exchanger - metabolism</subject><subject>Transfection</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUk2LFDEQDaK44-o_EAl48dJtJel89EUYZnUVBxR27yGdTkvG7s6YpBfm35tmVhf2ohASqHr18qpeIfSaQE2AiPeH2pp5dLmmQGQNpAYmnqANUZJWslXwFG2AQVMxxfgFepHSAQB4I_lzdEEVBco43SC_nfwcsLG-xzmaOR1DzC7im_2OqS3DxximkF3Ck8smleMTDgOew1ylyYwjtq5c4zL_wEWOLZVrIOHuVDizvzPZl9T3q6_kJXo2mDG5V_fvJbr99PF297naf7v-stvuK8tbyJW1jDrWdLwH1VDRD0xK0TFRglyYIrwjlouS6MxAemFE24tGqFaI3g3csUv07kxblP9aXMp68mnVZGYXlqSJUkRyIgn9D6hooQXWtgX69hH0EJY4lz4KSirFqZSkoJozysaQUnSDPkY_mXjSBPRqmj7os2l6NU0D0cW0UvbmnnzpJtf_LfrjUgF8OANcmdudd1En612Zdu-js1n3wf_rh8cEdvSzt2b86U4uPfSiE9Wgb9bFWfeGSAYgFWW_AV39vNg</recordid><startdate>20170501</startdate><enddate>20170501</enddate><creator>Wang, Yanhui</creator><creator>Fu, Li</creator><creator>Cui, Minqing</creator><creator>Wang, Yongbin</creator><creator>Xu, Yan</creator><creator>Li, Molin</creator><creator>Mi, Jun</creator><general>Elsevier B.V</general><general>Elsevier Limited</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>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5788-3965</orcidid></search><sort><creationdate>20170501</creationdate><title>Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1</title><author>Wang, Yanhui ; Fu, Li ; Cui, Minqing ; Wang, Yongbin ; Xu, Yan ; Li, Molin ; Mi, Jun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c590t-cc32e34b5d08426df3776b362e356a282b1c5626dbaf1d6a69d6468966def5e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>3-Phosphoinositide-Dependent Protein Kinases - genetics</topic><topic>3-Phosphoinositide-Dependent Protein Kinases - metabolism</topic><topic>A549 Cells</topic><topic>Adenocarcinoma - enzymology</topic><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - pathology</topic><topic>Adenocarcinoma of Lung</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Carcinoma, Non-Small-Cell Lung - enzymology</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Carcinoma, Non-Small-Cell Lung - secondary</topic><topic>Cell Movement</topic><topic>Conflicts of interest</topic><topic>Enzyme Activation</topic><topic>Epithelial-Mesenchymal Transition</topic><topic>Glutamic Acid - deficiency</topic><topic>Glutamine</topic><topic>Grants</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Histidine - deficiency</topic><topic>Humans</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - enzymology</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - pathology</topic><topic>Medical prognosis</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Metastasis</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>NSCLC</topic><topic>PDK1</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Pulmonary arteries</topic><topic>Real time</topic><topic>Signal Transduction</topic><topic>SLC38A3</topic><topic>Sodium-Calcium Exchanger - genetics</topic><topic>Sodium-Calcium Exchanger - metabolism</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Yanhui</creatorcontrib><creatorcontrib>Fu, Li</creatorcontrib><creatorcontrib>Cui, Minqing</creatorcontrib><creatorcontrib>Wang, Yongbin</creatorcontrib><creatorcontrib>Xu, Yan</creatorcontrib><creatorcontrib>Li, Molin</creatorcontrib><creatorcontrib>Mi, Jun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Yanhui</au><au>Fu, Li</au><au>Cui, Minqing</au><au>Wang, Yongbin</au><au>Xu, Yan</au><au>Li, Molin</au><au>Mi, Jun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2017-05-01</date><risdate>2017</risdate><volume>393</volume><spage>8</spage><epage>15</epage><pages>8-15</pages><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>Abstract Background Tumor metastasis is a finely-tuned pathological process coupled to metabolic reprogramming that includes both glutamine and glucose. The solute carrier SLC38A3, a member of amino acid/polyamine/organocation (APC) superfamily, is an l -glutamine transporter. It is not clear whether SLC38A3 involves the metastasis of NSCLC (non small cell lung cancer). Methods The scratch test and transwell assay were used to determine the ability of NSCLC to migrate. Cellular amino acids content was determined by mass spectrometry. The cellular response to glutamine/histidine deficiency was evaluated in A549 cells. The expression of SLC38A3 was assayed in clinical NSCLC and paratumor tissues by histoimmunochemistry staining. A nude mouse model of NSCLC metastasis was developed by tail vein injection of tumor cells. Results SLC38A3 was upregulated in metastatic NSCLC cells and its expression was correlated with prognosis of NSCLC patients. SLC38A3 overexpression promoted epithelial – mesenchymal transition (EMT) and migration of HCC827 and A549 human lung adenocarcinoma cells, and accelerated tumor metastasis in mice. We found that SLC38A3 decreased the cellular concentrations of glutamine and histidine, and the deficiency of glutamine or histidine activated PDK1/AKT signaling that in turn, triggered NSCLC metastasis. Conclusions SLC38A3 activated PDK1/AKT signaling and promoted metastasis of NSCLC through regulating glutamine and histidine transport, suggesting SLC38A3 as a potential therapeutic target for treatment of NSCLC.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>28202352</pmid><doi>10.1016/j.canlet.2017.01.036</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-5788-3965</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 3-Phosphoinositide-Dependent Protein Kinases - genetics 3-Phosphoinositide-Dependent Protein Kinases - metabolism A549 Cells Adenocarcinoma - enzymology Adenocarcinoma - genetics Adenocarcinoma - pathology Adenocarcinoma of Lung Amino acids Animals Carcinoma, Non-Small-Cell Lung - enzymology Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - secondary Cell Movement Conflicts of interest Enzyme Activation Epithelial-Mesenchymal Transition Glutamic Acid - deficiency Glutamine Grants Hematology, Oncology and Palliative Medicine Histidine - deficiency Humans Lung cancer Lung Neoplasms - enzymology Lung Neoplasms - genetics Lung Neoplasms - pathology Medical prognosis Metabolism Metabolites Metastasis Mice, Inbred BALB C Mice, Nude NSCLC PDK1 Phosphorylation Proteins Proto-Oncogene Proteins c-akt - metabolism Pulmonary arteries Real time Signal Transduction SLC38A3 Sodium-Calcium Exchanger - genetics Sodium-Calcium Exchanger - metabolism Transfection |
| title | Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1 |
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