Total coumarins of Pileostegia tomentella induces cell death in SCLC by reprogramming metabolic patterns, possibly through attenuating β-catenin/AMPK/SIRT1

Chinese Medicine

Research

Li Wang¹  Hua Su¹  Li Li¹  Ying Liu¹  Fucui Zhu²  Ying Li³  Kun Wu⁴  Guoshou Lu⁵  Xiaoxi Hu⁵  Lu Lu⁶ 

[1] Department of Pharmacology, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, 530001, Nanning, Guangxi, People’s Republic of China;Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, 530001, Nanning, Guangxi, People’s Republic of China;Department of Pharmacology, School of Pharmacy, Guangxi Medical University, 530021, Nanning, Guangxi, People’s Republic of China;Department of Pharmacy, Guangxi Orthopaedics and Traumatology Hospital, 530012, Nanning, Guangxi, People’s Republic of China;Departments of Hepatobiliary and Gastrointestinal Surgery, Minzu Hospital of Guangxi Zhuang Autonomous Region, 530021, Nanning, Guangxi, People’s Republic of China;Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, 530001, Nanning, Guangxi, People’s Republic of China;Department of Chemistry, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, 530001, Nanning, Guangxi, People’s Republic of China;School of Medicine & Health, Guangxi Vocational & Technical Institute of Industry, 530001, Nanning, Guangxi, People’s Republic of China;

关键词: Yao medicine;    Pileostegia tomentella;    Total coumarins;    SCLC;    Metabolism reprogramming;   

DOI  :  10.1186/s13020-022-00703-7

 received in 2022-10-29, accepted in 2022-12-20,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundSmall-cell lung cancer (SCLC) is a high malignant and high energy-consuming type of lung cancer. Total coumarins of Pileostegia tomentella (TCPT) from a traditional folk medicine of Yao minority, is a potential anti-cancer mixture against SCLC, but the pharmacological and molecular mechanism of TCPT remains largely unknown.MethodsScreening of viability inhibition of TCPT among 7 cell lines were conducted by using CCK-8 assays. Anti-proliferative activities of TCPT in SCLC were observed by using colony formation and flow cytometry assays. Morphological changes were observed by transmission electron microscope and Mito-Tracker staining. High Throughput RNA-seq analysis and bio-informatics analysis were applied to find potential targeted biological and signaling pathways affected by TCPT. The mRNA expression of DEGs and protein expression of signalling proteins and metabolic enzymes were verified by qPCR and Western blot assays. Activity of rate-limiting enzymes and metabolite level were detected by corresponding enzyme activity and metabolites kits. Xenograft nude mice model of SCLC was established to observe the in vivo inhibition, metabolism reprogramming and mechanism of TCPT.ResultsTCPT treatment shows the best inhibition in SCLC cell line H1688 rather than other 5 lung cancer cell lines. Ultrastructural investigation indicates TCPT induces mitochondria damage such as cytoplasm shrinkage, ridges concentration and early sight of autolysosome, as well as decrease of membrane potential. Results of RNA-seq combined bio-informatics analysis find out changes of metabolism progression affected the most by TCPT in SCLC cells, and these changes might be regulated by β-catenin/AMPK/SIRT1 axis. TCPT might mainly decline the activity and expression of rate-limiting enzymes, OGDH, PDHE1, and LDHA/B to reprogram aerobic oxidation pattern, resulting in reduction of ATP production in SCLC cells. Xenograft nude mice model demonstrates TCPT could induce cell death and inhibit growth in vivo. Assimilate to the results of in vitro model, TCPT reprograms metabolism by decreasing the activity and expression of rate-limiting enzymes (OGDH, PDHE1, and LDHA/B), and attenuates the expression of β-catenin, p-β-catenin, AMPK and SIRT1 accordance with in vitro data.ConclusionOur results demonstrated TCPT induces cell death of SCLC by reprograming metabolic patterns, possibly through attenuating master metabolic pathway axis β-catenin/AMPK/SIRT1.

【 授权许可】

CC BY   
© The Author(s) 2023

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