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

Publisher: BioMed Central Country of Publication: England NLM ID: 100968547 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-230X (Electronic) Linking ISSN: 1471230X NLM ISO Abbreviation: BMC Gastroenterol Subsets: MEDLINE

Original Publication: London : BioMed Central, [2001-

Stomach Neoplasms*/pathology ; Stomach Neoplasms*/drug therapy ; Stomach Neoplasms*/metabolism ; Stomach Neoplasms*/genetics ; Neoplastic Stem Cells*/drug effects ; Neoplastic Stem Cells*/metabolism ; Neoplastic Stem Cells*/pathology ; AC133 Antigen*/metabolism ; AC133 Antigen*/genetics ; B7-H1 Antigen*/metabolism ; Cell Proliferation*/drug effects ; Cell Adhesion Molecules, Neuronal*/metabolism ; Cell Adhesion Molecules, Neuronal*/genetics; Humans ; Animals ; Cell Line, Tumor ; Mice ; Fetal Proteins/metabolism ; Fetal Proteins/genetics ; Xenograft Model Antitumor Assays ; Tumor Microenvironment/drug effects ; Activated-Leukocyte Cell Adhesion Molecule/metabolism ; Activated-Leukocyte Cell Adhesion Molecule/genetics ; Phenotype ; Cell Movement/drug effects ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Mice, Nude ; Antigens, CD/metabolism

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).)

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2021JY-64 Shaanxi Provincial People's Hospital Science and Technology Talent Support Program

Keywords: CD133+/CD166+; Gastric cancer stem cell; PD-L1; Rhaponticin

0 (AC133 Antigen)
0 (B7-H1 Antigen)
0 (CD274 protein, human)
0 (Cell Adhesion Molecules, Neuronal)
0 (ALCAM protein, human)
0 (PROM1 protein, human)
0 (Fetal Proteins)
0 (Activated-Leukocyte Cell Adhesion Molecule)
0 (Antineoplastic Agents)
0 (Antigens, CD)

Date Created: 20241122 Date Completed: 20241122 Latest Revision: 20241124

20241126

PMC11583647

10.1186/s12876-024-03512-4

39573998