Work

Thiostrepton Suppresses the Progression of Rhabdomyosarcoma by Inhibiting the PI3K‐AKT Signaling Pathway

Year: 2025

Type: article

Abstract: ABSTRACT Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma with 5‐year survival below 30% in high‐risk/metastatic cases, was investigated through integrated bioinformatics analysis (identifying 269 conserved differentially expressed genes in GEO datasets GSE28511/GSE141690) and experimentally validated thiostrepton (TST), a ribosomal‐targeting antibiotic, as a potent therapeutic candidate via Connectivity Map analysis (p < 0.05, score ≈ −1). In‐vitro studies demonstrated TST's dose‐/time‐dependent suppression of RMS proliferation (IC50 4.986–9.764 μmol/L), migration and invasion, G0/G1 cell cycle arrest, and apoptosis induction. In vivo, TST (3.4 mg/mL, 4 weeks) significantly inhibited tumor growth (p < 0.05 vs. phosphate buffered saline [PBS]) without organ toxicity. RNA sequencing identified the phosphatidylinositol 3‐kinase/protein kinase B (PI3K‐AKT) pathway as the primary suppressed pathway (False Discovery Rate [FDR] < 0.05), with concurrent downregulation of downstream regulators (AKT, JAK, CDKs). This was confirmed by PI3K activator 740 Y‐P rescue experiments, which partially reversed the effects of TST (p < 0.05). These findings establish TST as a multi‐mechanism PI3K‐AKT inhibitor for refractory RMS while validating Connectivity Map (Cmap)‐driven drug repurposing for pediatric oncology.

Source: Pediatric Discovery

DOI: 10.1002/pdi3.70014