Sestrin2 and sestrin3 suppress NK-92 cell-mediated cytotoxic activity on ovarian cancer cells through AMPK and mTORC1 signaling

Abstract

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.