mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer
Oncogenic activation of the mammalian target of rapamycin complex 1 (mTORC1) leads to endometrial cancer cell growth and proliferation. Sestrin2 (SESN2), a highly conserved stress-inducible protein, is involved in homeostatic regulation via inhibition of reactive oxygen species (ROS) and mTORC1. How...
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| Veröffentlicht in: | Cancers 2020-09, Vol.12 (9), p.2515 |
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| creator | Shin, Jiha Bae, Jeongyun Park, Sumi Kang, Hyun-Goo Shin, Seong Min Won, Gunho Kim, Jong-Seok Cho, Ssang-Goo Choi, Youngsok Oh, Sang-Muk Shin, Jongdae Kim, Jeong Sig Park, Hwan-Woo |
| description | Oncogenic activation of the mammalian target of rapamycin complex 1 (mTORC1) leads to endometrial cancer cell growth and proliferation. Sestrin2 (SESN2), a highly conserved stress-inducible protein, is involved in homeostatic regulation via inhibition of reactive oxygen species (ROS) and mTORC1. However, the role of SESN2 in human endometrial cancer remains to be investigated. Here, we investigated expression, clinical significance, and underlying mechanisms of SESN2 in endometrial cancer. SESN2 was upregulated more in endometrial cancer tissues than in normal endometrial tissues. Furthermore, upregulation of SESN2 statistically correlated with shorter overall survival and disease-free survival in patients with endometrial cancer. SESN2 expression strongly correlated with mTORC1 activity, suggesting its impact on prognosis in endometrial cancer. Additionally, knockdown of SESN2 promoted cell proliferation, migration, and ROS production in endometrial cancer cell lines HEC-1A and Ishikawa. Treatment of these cells with mTOR inhibitors reversed endometrial cancer cell proliferation, migration, and epithelial–mesenchymal transition (EMT) marker expression. Moreover, in a xenograft nude mice model, endometrial cancer growth increased by SESN2 knockdown. Thus, our study provides evidence for the prognostic significance of SESN2, and a relationship between SESN2, the mTORC1 pathway, and endometrial cancer growth, suggesting SESN2 as a potential therapeutic target in endometrial cancer. |
| doi_str_mv | 10.3390/cancers12092515 |
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Sestrin2 (SESN2), a highly conserved stress-inducible protein, is involved in homeostatic regulation via inhibition of reactive oxygen species (ROS) and mTORC1. However, the role of SESN2 in human endometrial cancer remains to be investigated. Here, we investigated expression, clinical significance, and underlying mechanisms of SESN2 in endometrial cancer. SESN2 was upregulated more in endometrial cancer tissues than in normal endometrial tissues. Furthermore, upregulation of SESN2 statistically correlated with shorter overall survival and disease-free survival in patients with endometrial cancer. SESN2 expression strongly correlated with mTORC1 activity, suggesting its impact on prognosis in endometrial cancer. Additionally, knockdown of SESN2 promoted cell proliferation, migration, and ROS production in endometrial cancer cell lines HEC-1A and Ishikawa. Treatment of these cells with mTOR inhibitors reversed endometrial cancer cell proliferation, migration, and epithelial–mesenchymal transition (EMT) marker expression. Moreover, in a xenograft nude mice model, endometrial cancer growth increased by SESN2 knockdown. Thus, our study provides evidence for the prognostic significance of SESN2, and a relationship between SESN2, the mTORC1 pathway, and endometrial cancer growth, suggesting SESN2 as a potential therapeutic target in endometrial cancer.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers12092515</identifier><identifier>PMID: 32899752</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Cancer ; Cell cycle ; Cell growth ; Cell migration ; Cell proliferation ; Development and progression ; Endometrial cancer ; Endometrium ; Gene expression ; Health aspects ; Hypoxia ; Kinases ; Liver cancer ; Mammals ; Medical prognosis ; Mesenchyme ; Metabolism ; Obesity ; Pathogenesis ; Phosphorylation ; Proteins ; Rapamycin ; Reactive oxygen species ; TOR protein ; Tumor cell lines ; Xenografts</subject><ispartof>Cancers, 2020-09, Vol.12 (9), p.2515</ispartof><rights>COPYRIGHT 2020 MDPI AG</rights><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-67accfd95783a18572ef736000645cbf6f06e2a0326a6ed65f8dbbdfece79da83</citedby><cites>FETCH-LOGICAL-c426t-67accfd95783a18572ef736000645cbf6f06e2a0326a6ed65f8dbbdfece79da83</cites><orcidid>0000-0001-8029-2004 ; 0000-0002-0998-5569 ; 0000-0002-0968-7932</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/PMC7565818/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565818/$$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>Shin, Jiha</creatorcontrib><creatorcontrib>Bae, Jeongyun</creatorcontrib><creatorcontrib>Park, Sumi</creatorcontrib><creatorcontrib>Kang, Hyun-Goo</creatorcontrib><creatorcontrib>Shin, Seong Min</creatorcontrib><creatorcontrib>Won, Gunho</creatorcontrib><creatorcontrib>Kim, Jong-Seok</creatorcontrib><creatorcontrib>Cho, Ssang-Goo</creatorcontrib><creatorcontrib>Choi, Youngsok</creatorcontrib><creatorcontrib>Oh, Sang-Muk</creatorcontrib><creatorcontrib>Shin, Jongdae</creatorcontrib><creatorcontrib>Kim, Jeong Sig</creatorcontrib><creatorcontrib>Park, Hwan-Woo</creatorcontrib><title>mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer</title><title>Cancers</title><description>Oncogenic activation of the mammalian target of rapamycin complex 1 (mTORC1) leads to endometrial cancer cell growth and proliferation. Sestrin2 (SESN2), a highly conserved stress-inducible protein, is involved in homeostatic regulation via inhibition of reactive oxygen species (ROS) and mTORC1. However, the role of SESN2 in human endometrial cancer remains to be investigated. Here, we investigated expression, clinical significance, and underlying mechanisms of SESN2 in endometrial cancer. SESN2 was upregulated more in endometrial cancer tissues than in normal endometrial tissues. Furthermore, upregulation of SESN2 statistically correlated with shorter overall survival and disease-free survival in patients with endometrial cancer. SESN2 expression strongly correlated with mTORC1 activity, suggesting its impact on prognosis in endometrial cancer. Additionally, knockdown of SESN2 promoted cell proliferation, migration, and ROS production in endometrial cancer cell lines HEC-1A and Ishikawa. Treatment of these cells with mTOR inhibitors reversed endometrial cancer cell proliferation, migration, and epithelial–mesenchymal transition (EMT) marker expression. Moreover, in a xenograft nude mice model, endometrial cancer growth increased by SESN2 knockdown. Thus, our study provides evidence for the prognostic significance of SESN2, and a relationship between SESN2, the mTORC1 pathway, and endometrial cancer growth, suggesting SESN2 as a potential therapeutic target in endometrial cancer.</description><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell migration</subject><subject>Cell proliferation</subject><subject>Development and progression</subject><subject>Endometrial cancer</subject><subject>Endometrium</subject><subject>Gene expression</subject><subject>Health aspects</subject><subject>Hypoxia</subject><subject>Kinases</subject><subject>Liver cancer</subject><subject>Mammals</subject><subject>Medical prognosis</subject><subject>Mesenchyme</subject><subject>Metabolism</subject><subject>Obesity</subject><subject>Pathogenesis</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Rapamycin</subject><subject>Reactive oxygen species</subject><subject>TOR protein</subject><subject>Tumor cell lines</subject><subject>Xenografts</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1PHSEUxUnTphrruluSbrqZyscAw6aJebW1iYnm-Vx1QXjMZYqZgVd4Y9L_vowarbK5JPzuuedwEfpIyRfONTlxNjrIhTKimaDiDTpkRLFGSt2-_e9-gI5LuSX1cE6VVO_RAWed1kqwQ_Rr2lyum2-wg9hD3ON1GgEnj6-h7HOIDIeI1zDMo92HOODNPKWMr3IaMpQSUlzY83myEZ_FPk1Qm-yIV_fOPqB33o4Fjh_rEbr5frZZnTcXlz9-rk4vGtcyuW-kss75XgvVcUs7oRh4xWX1K1vhtl56IoFZwpm0EnopfNdvt70HB0r3tuNH6OuD7m7eTtC7miPb0exymGz-a5IN5uVLDL_NkO6MElJ0dBH4_CiQ05-5JjdTKA7G0UZIczGsbSnrKBG6op9eobdpzrHGu6dI_VVCn6nBjmBC9KnOdYuoOZW8jtS6W7ROHiiXUykZ_JNlSsyyYfNqw_wfi92Y0A</recordid><startdate>20200904</startdate><enddate>20200904</enddate><creator>Shin, Jiha</creator><creator>Bae, Jeongyun</creator><creator>Park, Sumi</creator><creator>Kang, Hyun-Goo</creator><creator>Shin, Seong Min</creator><creator>Won, Gunho</creator><creator>Kim, Jong-Seok</creator><creator>Cho, Ssang-Goo</creator><creator>Choi, Youngsok</creator><creator>Oh, Sang-Muk</creator><creator>Shin, Jongdae</creator><creator>Kim, Jeong Sig</creator><creator>Park, Hwan-Woo</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</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/0000-0001-8029-2004</orcidid><orcidid>https://orcid.org/0000-0002-0998-5569</orcidid><orcidid>https://orcid.org/0000-0002-0968-7932</orcidid></search><sort><creationdate>20200904</creationdate><title>mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer</title><author>Shin, Jiha ; 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Sestrin2 (SESN2), a highly conserved stress-inducible protein, is involved in homeostatic regulation via inhibition of reactive oxygen species (ROS) and mTORC1. However, the role of SESN2 in human endometrial cancer remains to be investigated. Here, we investigated expression, clinical significance, and underlying mechanisms of SESN2 in endometrial cancer. SESN2 was upregulated more in endometrial cancer tissues than in normal endometrial tissues. Furthermore, upregulation of SESN2 statistically correlated with shorter overall survival and disease-free survival in patients with endometrial cancer. SESN2 expression strongly correlated with mTORC1 activity, suggesting its impact on prognosis in endometrial cancer. Additionally, knockdown of SESN2 promoted cell proliferation, migration, and ROS production in endometrial cancer cell lines HEC-1A and Ishikawa. Treatment of these cells with mTOR inhibitors reversed endometrial cancer cell proliferation, migration, and epithelial–mesenchymal transition (EMT) marker expression. Moreover, in a xenograft nude mice model, endometrial cancer growth increased by SESN2 knockdown. Thus, our study provides evidence for the prognostic significance of SESN2, and a relationship between SESN2, the mTORC1 pathway, and endometrial cancer growth, suggesting SESN2 as a potential therapeutic target in endometrial cancer.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>32899752</pmid><doi>10.3390/cancers12092515</doi><orcidid>https://orcid.org/0000-0001-8029-2004</orcidid><orcidid>https://orcid.org/0000-0002-0998-5569</orcidid><orcidid>https://orcid.org/0000-0002-0968-7932</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Cancer Cell cycle Cell growth Cell migration Cell proliferation Development and progression Endometrial cancer Endometrium Gene expression Health aspects Hypoxia Kinases Liver cancer Mammals Medical prognosis Mesenchyme Metabolism Obesity Pathogenesis Phosphorylation Proteins Rapamycin Reactive oxygen species TOR protein Tumor cell lines Xenografts |
| title | mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer |
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