Dihydroartemisinin, a potential PTGS1 inhibitor, potentiated cisplatin-induced cell death in non-small cell lung cancer through activating ROS-mediated multiple signaling pathways

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2024-05, Vol.51, p.100991-100991, Article 100991
• Main Authors: Ni, Lianli, Zhu, Xinping, Zhao, Qi, Shen, Yiwei, Tao, Lu, Zhang, Ji, Lin, Han, Zhuge, Weishan, Cho, Young-Chang, Cui, Ri, Zhu, Wangyu
• Format: Article
• Language: English
• Subjects: Apoptosis; Artemisinins; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Death; Cell Line, Tumor; Cisplatin; Cisplatin - pharmacology; Cyclooxygenase 1 - metabolism; Cyclooxygenase 1 - pharmacology; Dihydroartemisinin (DHA); Endoplasmic reticulum (ER) stress; Humans; Lung Neoplasms - pathology; Mitogen-activated protein kinases (MAPK); Original Research; p38 Mitogen-Activated Protein Kinases - metabolism; Prostaglandin G/H synthase 1 (PTGS1); Reactive oxygen species (ROS); Reactive Oxygen Species - metabolism; Signal Transduction
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2024.100991

•Combined therapy with DHA and cisplatin exerts synergistic anti-NSCLC activity through activating ROS-mediated ER stress, JNK and p38 MAPK signaling pathways both in vitro and vivo.•PTGS1 is identified as a potential novel target of DHA. Knockdown of PTGS1 enhanced DHA-induced cell death in NSCLC cells through stimulating ROS-mediated ER stress, JNK and p38 MAPK signaling pathways. Dihydroartemisinin (DHA) exerts an anti-tumor effect in multiple cancers, however, the molecular mechanism of DHA and whether DHA facilitates the anti-tumor efficacy of cisplatin in non-small cell lung cancer (NSCLC) are unclear. Here, we found that DHA potentiated the anti-tumor effects of cisplatin in NSCLC cells by stimulating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 MAPK signaling pathways both in vitro and in vivo. Of note, we demonstrated for the first time that DHA inhibits prostaglandin G/H synthase 1 (PTGS1) expression, resulting in enhanced ROS production. Importantly, silencing PTGS1 sensitized DHA-induced cell death by increasing ROS production and activating ER-stress, JNK and p38 MAPK signaling pathways. In summary, our findings provided new experimental basis and therapeutic prospect for the combined therapy with DHA and cisplatin in some NSCLC patients. [Display omitted]