a. Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116000, China;
b. Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, College of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China;
c. Research & Production Department, Dalian Huali Jingang Pharmaceutical Co., Ltd., Dalian, 116110, Liaoning, China;
d. Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China;
e. Shenzhen Bao'an Authentic TCM Therapy Hospital, Shenzhen, Guangdong, 518101, China
Funds:
This work was supported by the National Natural Science Foundation of China (Grant No.: 82225048), the Dalian Science and Technology Leading Talents Project, China (Grant No.: 2019RD15), and Sanming Project of Medicine in Shenzhen, China (Grant No.: SZZYSM202106004).
Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors, including non-small cell lung cancer (NSCLC). However, its detailed molecular mechanism has not been adequately demonstrated. In this research, it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft (PDX) model. Mechanistically, employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis (MST), microRNA-145-5p (miR-145-5p) was pinpointed as a critical target through which elemene exerts its anti-tumor effects. Interestingly, elemene serves as a binding stabilizer for miR-145-5p, demonstrating a strong binding affinity (KD = 0.39 ±0.17 μg/mL) and preventing its degradation both in vitro and in vivo, while not interfering with the synthesis of the primary microRNA transcripts (pri-miRNAs) and precursor miRNAs (pre-miRNAs). The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA, subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated protein kinase kinase kinase 3 (MAP3K3)/nuclear factor kappaB (NF-κB) pathway. Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs.