Tricin Inhibits Human Osteosarcoma Cell Metastasis via Suppression of ZNF503 and the PI3K–PIP3–Akt Pathway

Osteosarcoma is the most common primary malignant bone tumor and is associated with a high mortality rate due to its pronounced metastatic potential. Although tricin has been proposed as a chemosensitizer in various malignancies, its anti-metastatic effect in osteosarcoma remains poorly characterized. This study investigated whether tricin suppresses metastasis in human osteosarcoma cells and explored the underlying molecular mechanisms. Our results revealed that tricin significantly inhibited the migration and invasion of U2OS and Saos-2 osteosarcoma cells and downregulated ZNF503 expression at both the mRNA and protein levels. Similarly, siRNA-mediated knockdown of ZNF503 suppressed cell migration, as confirmed by immunofluorescence analysis. Tricin treatment also reduced phosphorylation of PI3K and Akt, without affecting the activation of ERK1/2, JNK1/2, or p38. Additionally, intracellular levels of PIP3 were diminished following tricin exposure. Notably, the Akt activator SC-79 significantly reversed tricin-induced suppression of both ZNF503 expression and cell migration in U2OS and Saos-2 cells. In conclusion, these findings suggest that ZNF503 inhibits osteosarcoma cell motility via the PI3K-PIP3-Akt signaling axis and that tricin exerts anti-metastatic effects by targeting this pathway. Tricin may therefore represent a promising therapeutic agent for inhibiting osteosarcoma metastasis.