Dihydroartemisinin inhibits tumor progress via blocking ROR1-induced STAT3-activation in non-small cell lung cancer

• Published in: International immunopharmacology 2024-05, Vol.133, p.112157, Article 112157
• Main Authors: Li, Yanping, Sun, Haoyi, Bai, Caihong, Hu, Youfan, Tang, Jingyi, Zhang, Yuxi, Chen, Jilan, Zhong, Zhanqiong, He, Yuping, Hu, Kaifeng, Yang, Jiahui
• Format: Article
• Language: English
• Subjects: Apoptosis; Cell cycle; DHA; NSCLC; ROR1; STAT3
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112157

[Display omitted] •DHA inhibited the tumor growth by inducing cell cycle arrest and promoting apoptosis in NSCLC cells.•DHA reduced the expression level of receptor tyrosine kinase (RTK)-like orphan receptor 1 (ROR1).•ROR1 played a crucial role in promoting the activity of STAT3 signaling.•ROR1 may serve as a crucial molecular target mediating DHA-induced STAT3 inhibition in NSCLC. In non-small cell lung cancer (NSCLC), identifying a component with certain molecular targets can aid research on cancer treatment. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin which induced the anti-cancer effects via the STAT3 signaling pathway, but the underlying molecular mechanism is still elusive. In this study, we first proved that DHA prohibits the growth of tumors both in vitro and in vivo. Data from transcriptomics showed that DHA reduced the expression level of the genes involved in cell cycle-promoting and anti-apoptosis, and most importantly, DHA restricted the expression level of receptor tyrosine kinase-like orphan receptor 1 (ROR1) which has been reported to have abnormal expression on tumor cells and had close interaction with STAT3 signaling. Then, we performed comprehensive experiments and found that DHA remarkably decreased the expression of ROR1 at both mRNA and protein levels and it also diminished the phosphorylation level of STAT3 in NSCLC cell lines. In addition, our data showed that exogenously introduced ROR1 could significantly enhance the phosphorylation of STAT3 while blocking ROR1 had the opposite effects indicating that ROR1 plays a critical role in promoting the activity of STAT3 signaling. Finally, we found that ROR1 overexpression could partially reverse the decreased activity of STAT3 induced by DHA which indicates that DHA-induced anti-growth signaling is conferred, at least in part, through blocking ROR1-mediated STAT3 activation. In summary, our study indicates that in NSCLC, ROR1 could be one of the critical molecular targets mediating DHA-induced STAT3 retardation.