Orientin inhibits cyclin E/cyclin A-CDK2 to induce growth arrest at senescence in human gastric cancer cells

Gastric cancer (GC) is a primary epithelial malignancy originating in the stomach. This research explored the influence and mechanism of Orientin on cellular senescence in GC. Orientin was predicted to regulate multiple cell cycle-related pathways, including cyclin-dependent protein kinase activity. Orientin docked with cyclin dependent kinase 2 (CDK2), cyclin A2 (CCNA2), cyclin E1 (CCNE1), and cyclin E2 (CCNE2) with binding energies of -9.1, -7.5, -7.2, and -8.3 kcal/mol, respectively. The IC 50 values of Orientin for AGS and HGC-27 cells were 24.33 μM and 39.28 μM, respectively. Orientin dose-dependently inhibited GC cell proliferation, promoted G0/G1 phase arrest, as well as downregulated CDK2, CCNA2, CCNE1, and CCNE2 expression. It enhanced senescence-associated β-galactosidase staining intensity, upregulated p16 and p21, and downregulated phosphorylated retinoblastoma (p-Rb). In vivo , Orientin also suppressed tumor progression, promoted p16 and p21 expression, and inhibited CCNE/CCNA-CDK2 signaling. Orientin exerts anti-cancer effects in GC through triggering cellular senescence and cell cycle arrest, likely via activating p16/p21-Rb signaling axis and inhibiting the CCNE/CCNA-CDK2 pathway. Download: Download high-res image (282KB) Download: Download full-size image