Dihydrotanshinone I induces necroptosis and cell cycle arrest in gastric cancer through the PTPN11/p38 pathway

In this study, MTT assays, apoptosis detection, immunofluorescence, and functional studies were used to elucidate the mechanisms underlying the effects of dihydrotanshinone I (DHT) on gastric cancer cells. Drug target prediction and analysis were conducted to identify potential targets of DHT. MTT assay revealed significant inhibition of AGS and HGC27 cells by DHT. Morphological changes, including nuclear shrinkage and the induction of necrotic cell death, were observed in DHT-treated gastric cancer cells, along with cell cycle arrest at the G2/M phase. Further analysis revealed potential targets of DHT, including PTPN11, which is highly expressed in gastric cancer cells. DHT treatment increased necrosis-related proteins (RIPK1/RIPK3/MLKL) and downregulated cell cycle-related proteins (CDC25C and CDK1) levels in gastric cancer cells. After DHT treatment, PTPN11 protein expression decreased. Furthermore, DHT significantly increased the phosphorylated p38/JNK protein level, with the phosphorylated p38 protein notably enriched in the nucleus. These functional studies indicate that PTPN11 plays a key role in mediating the effects of DHT, including cell cycle regulation and necrosis induction. In conclusion, PTPN11 is a central target through which DHT affects gastric cancer cells, regulating downstream pathways involved in necroptosis (p38/RIPK1/RIPK3/MLKL/JNK) and cell cycle arrest (p38/CDC25C/CDK1).