Rhaponticin suppresses the stemness phenotype of gastric cancer stem-like cells CD133+/CD166 + by inhibiting programmed death-ligand 1.

Autor: Li Y; Department of Gastroenterology, Shaanxi Provincial People's Hospital, No. 256 Friendship West Road, Beilin District, Xi'an, Shaanxi, 710068, China. liyulong1331@163.com., Zhang Y; Department of Gastroenterology, Shaanxi Provincial People's Hospital, No. 256 Friendship West Road, Beilin District, Xi'an, Shaanxi, 710068, China., Tang J; Department of Gastroenterology, Shaanxi Provincial People's Hospital, No. 256 Friendship West Road, Beilin District, Xi'an, Shaanxi, 710068, China.
Jazyk: angličtina
Zdroj: BMC gastroenterology [BMC Gastroenterol] 2024 Nov 21; Vol. 24 (1), pp. 423. Date of Electronic Publication: 2024 Nov 21.
DOI: 10.1186/s12876-024-03512-4
Abstrakt: Background: Gastric cancer stem cells (GCSCs) are key contributors to tumorigenesis, recurrence and metastasis, complicating gastric cancer (GC) treatment. Rhaponticin (RA), a potential novel anticancer drug, has unexplored effects on GCSCs.
Methods: GCSCs were isolated using CD133 and CD166 markers with magnetic bead separation method and then evaluated their response to the IC50 concentrations of RA (16.90 µg/mL for BGC-823 and 22.18 µg/mL for SGC-7901), and effects on cell proliferation, migration, invasion, and stemness were measured. We analyzed the GCSC-related microarray dataset GSE111556 and explored RA's role in restoring programmed cell death ligand 1 (PD-L1) function in CD133+/CD166 + cells post-PD-L1 knockdown. RA's impact on tumour growth and immune microenvironment was assessed in a xenograft mouse model.
Results: The CD133+/CD166 + subpopulation exhibited stem-like characteristics, with the highest proportion in BGC-823 (38.85%) and SGC-7901 (43.81%) cells. These cells formed tumour spheres and had increased expression of stemness markers Sox2 and Oct-4 (compared to the parental cell line, P < 0.001). RA treatment showed no toxicity to normal GES-1 cells but reduced the viability of CD133+/CD166 + cells in a dose-dependent manner, with IC50 values of 16.90 µg/ml for BGC-823 and 22.18 µg/ml for SGC-7901. RA also decreased the proportion of CD133+/CD166 + cells and their stem-like properties (P < 0.001). Analysis of the GEO database identified PD-L1 as a key target gene of RA, with high expression in GC tissues. Knocking down PD-L1 in CD133+/CD166 + cells and introducing RA did not significantly change PD-L1 expression (P>0.05), suggesting RA's effect may be PD-L1 dependent. In a xenograft mouse model, the tumour size in the RA treatment group was approximately one-sixth that of the CD133+/CD166 + group (P < 0.001). Post-RA treatment, there was an elevation in the expression levels of CD4 and CD8, alongside a reduction in PD-L1 expression (P < 0.001).
Conclusions: RA suppresses GCSC stem - like phenotype by inhibiting PD - L1 and enhancing T cell tumour infiltration in the studied models. These findings suggest that RA may have potential for further exploration as a candidate for GC treatment, but extensive preclinical and clinical studies are required to determine its true therapeutic value.
Competing Interests: Declarations. Ethical approval: Animal experiments were approved and supervised by the animal ethics committee of Shaanxi Provincial People’s Hospital. This study adheres to relevant ethical and operational standards to ensure that animals are properly cared for and protected during the experimental process. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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