BMSCs promote apoptosis in glioma cells by inhibiting STAT3 phosphorylation

Bone marrow mesenchymal stem cells (BMSCs) show promise in glioma therapy, but the underlying mechanisms remain unclear. Signal transducer and activator of transcription 3 (STAT3) is a key oncogenic driver in glioma; however, whether BMSCs exert anti-glioma effects through STAT3 modulation requires further investigation.

To investigate whether BMSCs promote glioma cell apoptosis by inhibiting STAT3 phosphorylation and to validate the causal role of STAT3 using a specific agonist.

C6 glioma-bearing rats were randomized into control, model, BMSC, positive control (MS-275) and STAT3 agonist (Colivelin) groups. BMSCs (1×10⁷ cells) were injected via the tail vein on days 14 and 17. Tumor growth, apoptosis, glial fibrillary acidic protein (GFAP) expression, basic fibroblast growth factor (bFGF)/vascular endothelial growth factor (VEGF) mRNA levels and STAT3/phosphorylated STAT3 (p-STAT3) expression were assessed by magnetic resonance imaging (MRI), histology, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, flow cytometry, immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. In-vitro validation was performed using BMSC-conditioned medium and the STAT3 inhibitor Stattic in C6 cells.

BMSC transplantation significantly reduced the tumor area and Ki-67 proliferation index, increased the number of apoptotic cells and the apoptotic rate (P < 0.01) and decreased p-STAT3 levels and the p-STAT3/STAT3 ratio (P < 0.01) without altering total STAT3 expression. Colivelin reversed BMSC-induced apoptosis. bFGF and VEGF mRNA levels were increased in the BMSC group (P < 0.01). In-vitro, BMSC-conditioned medium suppressed STAT3 phosphorylation and induced apoptosis, effects that were enhanced by Stattic.

BMSCs promote apoptosis in glioma cells by inhibiting STAT3 phosphorylation. The reversal of these effects by a STAT3 agonist confirms the causal role of STAT3 inhibition. These findings identify STAT3 as a key therapeutic target for BMSC-based glioma therapy.