Salidroside regulates tumor microenvironment of non-small cell lung cancer via Hsp70/Stub1/Foxp3 pathway in Tregs

• Published in: BMC cancer Vol. 23; no. 1; p. 717
• Main Authors: Wen, Zexin, Liu, Tong, Zhang, Yanli, Yue, Qiujuan, Meng, Hang, He, Yijie, Yang, Yi, Li, Minghao, Zheng, Jianwen, Lin, Wei
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 01.08.2023; BioMed Central; BMC
• Subjects: Analysis; Animals; Antibodies; Antitumor activity; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Care and treatment; CD4 antigen; Cells; Diagnosis; Flow cytometry; Forkhead Transcription Factors - metabolism; Foxp3 protein; Heat shock proteins; Hsp70 protein; Immunological tolerance; Interleukin 10; Ki-67 antigen; Laboratory animals; Ligases; Localization; Lung cancer; Lung cancer, Non-small cell; Lung cancer, Small cell; Lung Neoplasms - metabolism; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Non-small cell lung cancer; Non-small cell lung carcinoma; Pathogens; Salidroside; Small cell lung carcinoma; Software; Stub1; T cells; T-Lymphocytes, Regulatory; Testing; Traditional Chinese medicine; Transcription factors; Treg; Tumor cells; Tumor Microenvironment; Tumor-infiltrating lymphocytes; Tumors; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Variance analysis; China; Beijing China; United States > US; Salidroside; Stub1; Tumor microenvironment; Non-small cell lung cancer; Treg
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-023-11036-5

The treatment of non-small cell lung cancer (NSCLC) is challenging due to immune tolerance and evasion. Salidroside (SAL) is an extract in traditional Chinese medicine and has a potential antitumor effect. However, the mechanism of SAL in regulating the immunological microenvironment of NSCLC is yet to be clarified. The mouse model with Lewis lung cancer cell line (3LL) in C57BL/6 mice was established. And then, the percentage of tumor-infiltrating T cell subsets including Treg was detected in tumor-bearing mice with or without SAL treatment. In vitro, the effect of SAL on the expression of IL-10, Foxp3 and Stub1 and the function of Treg were detected by flow cytometry. Network pharmacology prediction and molecular docking software were used to predict the target of SAL and intermolecular interaction. Furthermore, the effect of SAL on the expression of Hsp70 and the co-localization of Stub1-Foxp3 in Treg was confirmed by flow cytometry and confocal laser microscopy. Finally, Hsp70 inhibitor was used to verify the above molecular expression. We discovered that SAL treatment inhibits the growth of tumor cells by decreasing the percentage of tumor-infiltrated CD4 Foxp3 T cells. SAL treatment downregulates the expression of Foxp3 in Tregs, but increases the expression of Stub1, an E3 ubiquitination ligase upstream of Foxp3, and the expression of Hsp70. Inhibiting the expression of Hsp70 reverses the inhibition of SAL on Foxp3 and disrupts the colocalization of Stub1 and Foxp3 in the nucleus of Tregs. SAL inhibits tumor growth by regulating the Hsp70/stub1/Foxp3 pathway in Treg to suppress the function of Treg. It is a new mechanism of SAL for antitumor therapy.