Sestrin2 and sestrin3 suppress NK-92 cell-mediated cytotoxic activity on ovarian cancer cells through AMPK and mTORC1 signaling
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Xuejin Wang1,*, Weifeng Liu2,*, Deyi Zhuang3, Shaoxian Hong4 and Jingfang Chen5
1Department of Reproductive Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
2Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
3Department of Neonatal, Children's Hospital of Fudan University Xiamen Branch (Xiamen Children's Hospital), Xiamen 361000, China
4Department of Pediatric Intensive Care Unit, Children's Hospital of Fudan University Xiamen Branch (Xiamen Children's Hospital), Xiamen 361000, China
5Department of Pediatrics, Children's Hospital of Fudan University Xiamen Branch (Xiamen Children's Hospital), Xiamen 361000, China
*These authors have contributed equally to this work
Jingfang Chen, email: [email protected]
Keywords: NK cells, ovarian cancer, sestrin, mTOR, AMPK
Received: July 18, 2017 Accepted: August 29, 2017 Published: October 04, 2017
Ovarian cancer is one of the major cancer types. NK-92 cell line, which has consistently and reproducibly high anti-tumor cytotoxicity, may be used for immunotherapy against ovarian cancer. Understanding the mechanisms that regulate the anti-tumor activity of NK-92 cells is important for developing novel therapeutic strategies. In the current study, using an ovarian cancer xenograft mouse model, we identified the up-regulation of sestrin2 (SESN2) and sestrin3 (SESN3) in intratumoral NK-92 cells. Lentivirus-transduced NK-92 cells, which overexpressed SESN2 or SESN3 after doxycycline treatment, exhibited less expression of activating receptors, perforin and granzyme B. Overexpression of SESN2 and SESN3 impaired tumoricidal effect of NK-92 cells both in vitro and in vivo. Furthermore, overexpression of SESN2 and SESN3 inhibited mTORC1 signaling while promoting AMPK signaling in NK-92 cells. Taken together, our data highlights the crucial effects of SESN2 and SESN3 on NK-92 cell-mediated anti-ovarian cancer activity. This study might be valuable for designing a novel therapeutic strategy for ovarian cancer.
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