Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway
Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of a...
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| Veröffentlicht in: | International journal of molecular sciences 2022-08, Vol.23 (15), p.8761 |
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| creator | Kim, Gyeongmi Jang, Se-Kyeong Kim, Yu Jin Jin, Hyeon-Ok Bae, Seunghee Hong, Jungil Park, In-Chul Lee, Jae Ho |
| description | Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer. |
| doi_str_mv | 10.3390/ijms23158761 |
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Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms23158761</identifier><identifier>PMID: 35955892</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Amino acids ; Bcl-2 protein ; Biosynthesis ; Cancer therapies ; Cell culture ; Cell cycle ; Cell growth ; Cell viability ; Drug dosages ; Glutamine ; Immunoblotting ; Kinases ; Lysine ; Mcl-1 protein ; Metabolism ; Ovarian cancer ; Paclitaxel ; Phosphorylation ; Protein synthesis ; Proteins ; Signal transduction ; Therapeutic targets ; TOR protein</subject><ispartof>International journal of molecular sciences, 2022-08, Vol.23 (15), p.8761</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-b0b7b3127c36caa29cebab750031a1762128704c85af9168029947a5452aac9e3</citedby><cites>FETCH-LOGICAL-c389t-b0b7b3127c36caa29cebab750031a1762128704c85af9168029947a5452aac9e3</cites><orcidid>0000-0002-3878-6059</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/PMC9369036/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9369036/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids></links><search><creatorcontrib>Kim, Gyeongmi</creatorcontrib><creatorcontrib>Jang, Se-Kyeong</creatorcontrib><creatorcontrib>Kim, Yu Jin</creatorcontrib><creatorcontrib>Jin, Hyeon-Ok</creatorcontrib><creatorcontrib>Bae, Seunghee</creatorcontrib><creatorcontrib>Hong, Jungil</creatorcontrib><creatorcontrib>Park, In-Chul</creatorcontrib><creatorcontrib>Lee, Jae Ho</creatorcontrib><title>Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway</title><title>International journal of molecular sciences</title><description>Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.</description><subject>Amino acids</subject><subject>Bcl-2 protein</subject><subject>Biosynthesis</subject><subject>Cancer therapies</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell viability</subject><subject>Drug dosages</subject><subject>Glutamine</subject><subject>Immunoblotting</subject><subject>Kinases</subject><subject>Lysine</subject><subject>Mcl-1 protein</subject><subject>Metabolism</subject><subject>Ovarian cancer</subject><subject>Paclitaxel</subject><subject>Phosphorylation</subject><subject>Protein synthesis</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>Therapeutic targets</subject><subject>TOR protein</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkUtPGzEUha2qqEDKrj_AUjdddMCPeDzeVKpG5aEgBSWBrXXHdRKnM55ge8JjyS9nQhCCru7VPZ-O7tFB6Bslx5wrcuJWTWScikLm9BM6oEPGMkJy-fndvo8OY1wRwjgT6gva50IJUSh2gJ4u_NJVLrnW43aOz-ouQeO8xdfrBP8snthofez1RxvxFZjaJbi39fbuYgJvLHYeT0fjG57NJni8geDA43KrBFzausYbB7iZjSclPZnmIzx1Cw-184veLi3v4OEr2ptDHe3R6xyg69M_s_I8uxyfXZS_LzPDC5WyilSy4pRJw3MDwJSxFVRSEMIpUJkzygpJhqYQMFc0LwhTaihBDAUDMMryAfq18113VWP_GutTgFqvg2sgPOgWnP6oeLfUi3ajFc8V4Xlv8OPVILS3nY1JNy6aPiJ423ZRM0kYLVjRwwP0_T901Xahz_1CESmYpLynfu4oE9oYg52_PUOJ3par35fLnwFTaJYW</recordid><startdate>20220806</startdate><enddate>20220806</enddate><creator>Kim, Gyeongmi</creator><creator>Jang, Se-Kyeong</creator><creator>Kim, Yu Jin</creator><creator>Jin, Hyeon-Ok</creator><creator>Bae, Seunghee</creator><creator>Hong, Jungil</creator><creator>Park, In-Chul</creator><creator>Lee, Jae Ho</creator><general>MDPI AG</general><general>MDPI</general><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/0000-0002-3878-6059</orcidid></search><sort><creationdate>20220806</creationdate><title>Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway</title><author>Kim, Gyeongmi ; Jang, Se-Kyeong ; Kim, Yu Jin ; Jin, Hyeon-Ok ; Bae, Seunghee ; Hong, Jungil ; Park, In-Chul ; Lee, Jae Ho</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-b0b7b3127c36caa29cebab750031a1762128704c85af9168029947a5452aac9e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Amino acids</topic><topic>Bcl-2 protein</topic><topic>Biosynthesis</topic><topic>Cancer therapies</topic><topic>Cell culture</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell viability</topic><topic>Drug dosages</topic><topic>Glutamine</topic><topic>Immunoblotting</topic><topic>Kinases</topic><topic>Lysine</topic><topic>Mcl-1 protein</topic><topic>Metabolism</topic><topic>Ovarian cancer</topic><topic>Paclitaxel</topic><topic>Phosphorylation</topic><topic>Protein synthesis</topic><topic>Proteins</topic><topic>Signal transduction</topic><topic>Therapeutic targets</topic><topic>TOR protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Gyeongmi</creatorcontrib><creatorcontrib>Jang, Se-Kyeong</creatorcontrib><creatorcontrib>Kim, Yu Jin</creatorcontrib><creatorcontrib>Jin, Hyeon-Ok</creatorcontrib><creatorcontrib>Bae, Seunghee</creatorcontrib><creatorcontrib>Hong, Jungil</creatorcontrib><creatorcontrib>Park, In-Chul</creatorcontrib><creatorcontrib>Lee, Jae Ho</creatorcontrib><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>Kim, Gyeongmi</au><au>Jang, Se-Kyeong</au><au>Kim, Yu Jin</au><au>Jin, Hyeon-Ok</au><au>Bae, Seunghee</au><au>Hong, Jungil</au><au>Park, In-Chul</au><au>Lee, Jae Ho</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway</atitle><jtitle>International journal of molecular sciences</jtitle><date>2022-08-06</date><risdate>2022</risdate><volume>23</volume><issue>15</issue><spage>8761</spage><pages>8761-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>35955892</pmid><doi>10.3390/ijms23158761</doi><orcidid>https://orcid.org/0000-0002-3878-6059</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Amino acids Bcl-2 protein Biosynthesis Cancer therapies Cell culture Cell cycle Cell growth Cell viability Drug dosages Glutamine Immunoblotting Kinases Lysine Mcl-1 protein Metabolism Ovarian cancer Paclitaxel Phosphorylation Protein synthesis Proteins Signal transduction Therapeutic targets TOR protein |
| title | Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway |
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