Artesunate-induced ATG5-related autophagy enhances the cytotoxicity of NK92 cells on endometrial cancer cells via interactions between CD155 and CD226/TIGIT

• Published in: International immunopharmacology 2021-08, Vol.97, p.107705-107705, Article 107705
• Main Authors: Zhang, Jie, Zhou, Long, Xiang, Jiang-Dong, Jin, Chun-Sheng, Li, Ming-Qing, He, Yin-Yan
• Format: Article
• Language: English
• Subjects: Anticancer properties; Apoptosis; Artemisinin; Artesunate; Artesunate - pharmacology; Artesunate - therapeutic use; Autophagy; Autophagy - drug effects; Autophagy - immunology; Autophagy-Related Protein 5 - genetics; Autophagy-Related Protein 5 - metabolism; Cancer; Carcinoma; CD 155; CD155; Cell Line, Tumor; Cell proliferation; Cell survival; Coculture Techniques; Cytotoxicity; degradation; Developed countries; dnam-1; Down-Regulation - drug effects; Drug Screening Assays, Antitumor; ENdometrial cancer; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - immunology; Endometrial Neoplasms - pathology; Endometrium; Farmakologi och toxikologi; Female; gene; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Humans; Immune checkpoint; Immunologi inom det medicinska området; Immunology; Immunology in the medical area; Killer Cells, Natural - immunology; Malaria; molecules; Natural killer cells; NK cell; overexpression; Phagocytosis; Pharmacology & Pharmacy; Pharmacology and Toxicology; qinghaosu; Receptors, Immunologic - metabolism; Receptors, Virus - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; Stimulators; tigit; Toxicity; Uterine cancer; Uterus; Vector-borne diseases
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.107705

•ART inhibits the proliferation, migration and promotes the apoptosis of UCEC cells.•ART-induced autophagy enhances the expression of CD155 in UCEC cells.•ART elevates level of CD155 partially through ATG5 in UCEC cells.•ART promotes the cytotoxicity of NK92 cells on UCEC cells.•ART modulates such effects via interactions between CD155 and CD226/TIGIT. Uterine corpus endometrial carcinoma (UCEC) is the most prevalent gynecologic cancer in developed countries and lacks efficient therapeutic strategies. Artesunate (ART), a well-modified derivate of artemisinin, exerts potent anti-cancer effects apart from its classical anti-malaria feature. Autophagy is a universal double-edged process in cell survival, and CD155 is a novel immune checkpoint highly expressed in numerous cancers. However, the relationships among ART, autophagy, and CD155 remain unclear in UCEC. In this study, we discovered that ART not only inhibited proliferation and migration, promoted apoptosis, but also induced autophagy in UCEC cells. Meanwhile, ART-induced autophagy elevated the level of CD155 in UCEC cells, thereby enhancing the cytotoxicity of natural killer cell line (NK92) by modulating the interactions between CD155 and its receptors in NK92 cells via upregulation of co-stimulator CD226 and downregulation of co-inhibitor TIGIT. Additionally, ART regulated CD155 partially via ATG5, and knockdown of ATG5 dampened the expression of CD155 in UCEC cells, thus decreasing the cytotoxicity of NK92 cells. Therefore, this study demonstrated the dual anti-cancer effects of ART as it could induce cell-killing directly and indirectly, which provides novel insights into the anti-cancer mechanisms of ART on UCEC.