OncoTargets and Therapy (Dec 2019)
Triterpenoid Saponins from Anemone flaccida Suppress Tumor Cell Proliferation by Regulating MAPK, PD1/PDL1, and STAT3 Signaling Pathways and Altering Cancer Metabolism
Abstract
Lintao Han,1 Shiqi Yao,2 Sa Cao,2 Guoyan Mo,1 Jingjing Li,1 Yan Cao,2 Fang Huang1 1Key Laboratory of Traditional Chinese Medicine Resource and Prescription, Ministry of Education, Wuhan, Hubei 430061, People’s Republic of China; 2College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, People’s Republic of ChinaCorrespondence: Yan CaoCollege of Pharmacy, Hubei University of Chinese Medicine, No. 1 Huang-Jia-Hu Road, Wuhan, Hubei 430065, People’s Republic of ChinaTel/Fax +86 27 68896121Email [email protected] HuangKey Laboratory of Traditional Chinese Medicine Resource and Prescription, Ministry of Education, No. 1 Tan-Hua-Lin Road, Wuhan, Hubei 430061, People’s Republic of ChinaTel/Fax +86 27 68890129Email [email protected]: Natural triterpenoid saponins isolated from Anemone flaccida Fr. Schmidt have exhibited anti-cancer properties and exerted remarkable inhibitory effects on tumor growth. Herein, we investigated the potential mechanism involved in the suppression of hepatocellular carcinoma (HCC) development by triterpenoid saponins in a mouse model.Methods: An HCC model was established in H22 tumor-bearing mice and triterpenoid saponins were administered at various doses. Immunofluorescence, flow cytometry, and western blot were performed to analyze the effect of triterpenoid saponins on immune response in tumor tissues. Metabolomic analysis was carried out to assess the metabolites involved in mediating the effect of triterpenoid saponins on tumor tissues.Results: Triterpenoid saponins induced anti-tumor immune response by decreasing the number of Treg cells, increasing that of B cells, natural killer cells, and CD3+/CD28+ T cells, and reducing the secretion of inflammatory factors including nuclear factor-κB, cyclooxygenase-2, and microsomal prostaglandin E synthase-1. In addition, triterpenoid saponins inhibited tumor growth and induced the apoptosis of HCC cells by blocking the activation of PD1/PD-L1, ERK1/2, p38 MAPK, JNK, and STAT3 signaling pathways. Furthermore, triterpenoid saponins regulated tumor immune response by upregulating a number of metabolites (including 1,3-diaminopropane, lauric acid, 2,4-diaminobutyric acid 2, and ribitol) and modulating the metabolism of histidine, arginine, proline, beta-alanine, glycine, serine, and threonine.Conclusion: The findings suggested that triterpenoid saponins interfered with multiple signaling cascades involved in tumorigenesis and tumor metabolism and have potential applications in HCC therapy.Keywords: triterpenoid saponins, hepatocellular carcinoma, immune response, MAPK, PD1/PD-L1, STAT3
