mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer
1
Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Korea
2
Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon 35365, Korea
3
Department Centers for Disease Control & Prevention, National Institute of Health, Cheongju 28159, Korea
4
Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea
5
Department of Biochemistry, Konyang University College of Medicine, Daejeon 35365, Korea
6
Department of Obstetrics and Gynecology, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2020, 12(9), 2515; https://doi.org/10.3390/cancers12092515
Received: 22 July 2020
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Revised: 17 August 2020
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Accepted: 26 August 2020
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Published: 4 September 2020
(This article belongs to the Section Molecular Cancer Biology)
Simple Summary
Mammalian target of rapamycin complex 1 (mTORC1), a key controller of growth and environmental stress signaling, is frequently activated in human cancers. Sestrin2 (SESN2), a highly conserved stress-inducible protein, is one of the negative feedback mechanisms for inhibiting chronic activation of mTORC1. This study aimed to investigate the expression and clinical implications of SESN2 in endometrial cancer using an in vitro and in vivo approach. The analysis indicated increased levels of SESN2 and mTORC1 pathway activity in cancer tissues than in normal tissues. High SESN2 expression correlated with shorter patient survival duration. However, lentiviral overexpression of SESN2 and mTOR inhibitors suppressed cancer cell proliferation, migration, and epithelial–mesenchymal transition. Our study provides strong evidence for prognostic significance of SESN2, and its association with mTORC1 pathway and endometrial cancer growth. Thus, the results identified SESN2 as a potential therapeutic target in 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. 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.
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Keywords:
endometrial cancer; sestrin2; mTORC1; proliferation; migration; reactive oxygen species (ROS)
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MDPI and ACS Style
Shin, J.; Bae, J.; Park, S.; Kang, H.-G.; Shin, S.M.; Won, G.; Kim, J.-S.; Cho, S.-G.; Choi, Y.; Oh, S.-M.; Shin, J.; Kim, J.S.; Park, H.-W. mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer. Cancers 2020, 12, 2515. https://doi.org/10.3390/cancers12092515
AMA Style
Shin J, Bae J, Park S, Kang H-G, Shin SM, Won G, Kim J-S, Cho S-G, Choi Y, Oh S-M, Shin J, Kim JS, Park H-W. mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer. Cancers. 2020; 12(9):2515. https://doi.org/10.3390/cancers12092515
Chicago/Turabian StyleShin, Jiha, Jeongyun Bae, Sumi Park, Hyun-Goo Kang, Seong M. Shin, Gunho Won, Jong-Seok Kim, Ssang-Goo Cho, Youngsok Choi, Sang-Muk Oh, Jongdae Shin, Jeong S. Kim, and Hwan-Woo Park. 2020. "mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer" Cancers 12, no. 9: 2515. https://doi.org/10.3390/cancers12092515
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