Abstract
Simple SummaryMammalian 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.
Highlights
Endometrial cancer is the most common malignant cancer of the female reproductive system, with an increasing incidence worldwide due to high risk factors, including increased obesity rates [1,2,3].Patients with endometrial cancer diagnosed at an early stage show good prognosis with high survival rates, while those diagnosed at late stage have limited treatment options and poor prognosis, with low survival rates [4,5]
We evaluated the mRNA expression of SESN2 in the surgical endometrial cancer tissue samples and normal endometrium samples using quantitative real-time polymerase chain reaction
These results suggest that SESN2 expression affects the prognosis in endometrial cancer
Summary
Endometrial cancer is the most common malignant cancer of the female reproductive system, with an increasing incidence worldwide due to high risk factors, including increased obesity rates [1,2,3].Patients with endometrial cancer diagnosed at an early stage show good prognosis with high survival rates, while those diagnosed at late stage have limited treatment options and poor prognosis, with low survival rates [4,5]. The mammalian target of rapamycin (mTOR), a serine/threonine kinase that regulates cell growth and metabolism, is frequently activated in human cancers [8,9]. It comprises two structurally and functionally distinct complexes—mTOR complex 1 (mTORC1) and mTORC2. The mTORC1 is activated by nutrients via the phosphoinositide 3-kinase (PI3K)/AKT pathway, which is the most common cancer-promoting signaling event [10,11]. Inhibition of the mTORC1 signaling pathway with an immunosuppressive drug, rapamycin, suggested mTORC1 to be a potential target for anti-cancer treatment [14,15]; molecular mechanisms of mTORC1 regulation in endometrial cancer cells remain poorly understood
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