ginkgolic-acid and Stomach-Neoplasms

The imbalance of SUMOylation is related to different cancers, including gastric cancer (GC). Ginkgolic acid (GA) inhibits the growth and invasion of many cancer cells, and it has been reported to restrain SUMOylation. However, the role of GA in GC and whether it functions through SUMOylation remains to be clarified. Our research revealed that GA (15:1) inhibited cell proliferation, migration, epithelial-mesenchymal transition (EMT) and overall protein SUMOylation in BGC823 and HGC27 cells. In addition, knockdown of SUMO1 (small ubiquitin-like modifier) instead of SUMO2/3 played a similar role to GA in cell behaviors. Besides, nuclear IGF-1R (insulin-like growth factor 1 receptor) expression was markedly upregulated in GC cells compared to normal gastric epithelial cells. GA prevented IGF-1R from binding to SUMO1, thereby suppressing its nuclear accumulation. Further research found that IGF-1R directly bound to SNAI2 (snail family zinc finger 2) promoter. The interference of IGF-1R downregulated the mRNA and protein levels of SNAI2, while the overexpression of SUMO1, IGF-1R and UBC9 (SUMO-conjugating enzyme) played the opposite role. Furthermore, the co-transfection of SUMO1, UBC9 and IGF-1R vectors or the overexpression of SNAI2 reversed the inhibitory effects of GA on cell proliferation, migration and EMT. Finally, GA impeded the growth of GC xenografts and decreased the expression of nuclear IGF-1R and SNAI2 in vivo. In conclusion, these findings demonstrated that GA hindered the progression of GC by inhibiting the SUMOylation of IGF-1R. Thus, GA might be a promising therapeutic for GC.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation; Humans; Mice; Mice, Nude; Receptor, IGF Type 1; RNA Interference; RNA, Small Interfering; Salicylates; Small Ubiquitin-Related Modifier Proteins; Snail Family Transcription Factors; Stomach Neoplasms; SUMO-1 Protein; Sumoylation; Transplantation, Heterologous

Gastric cancer is a frequently occurring cancer with high mortality each year worldwide. Finding new and effective therapeutic strategy against human gastric cancer is still urgently required. Ginkgolic acid (GA), a botanical drug, is extracted from the seed coat of Ginkgo biloba L. with various bioactive properties, including anti-tumor. Unfortunately, if GA has antitumor effect on human gastric cancer and the underlying molecular mechanisms have yet to be investigated. In the present study, we found that GA markedly reduced the gastric cancer cell viability. Furthermore, GA treatment led to the reduced migration ability of gastric cancer cells, which was associated with the decreased protein expression levels of Rho-associated protein kinase 1 (ROCK1), matrix metalloproteinase-2 (MMP-2), MMP-9 and α-smooth muscle actin (α-SMA). In addition, GA dose-dependently induced apoptosis in gastric cancer cells through activating Caspase-9/-3 and poly(ADP-Ribose) polymerase (PARP), which was along with the reduced Bcl-2 and Bcl-xl expression levels, and the elevated Bax and Bad levels. Consistently, Cyto-c protein expression in cytoplasm was also up-regulated by GA. Moreover, the production of reactive oxygen species (ROS) was significantly induced by GA. The activation of signal transducer and activator of transcription 3/janus kinase 2 (Stat3/JAK2) signaling pathway was inhibited by GA treatment. Intriguingly, blocking Stat3/JAK2 activation could further promote apoptosis and reduce cell viability induced by GA. However, GA-induced cell death was clearly abolished by ROS scavenger NAC, while the activation of Stat3/JAK2 signaling was restored by NAC. In vivo, GA showed effective role in reducing gastric tumor growth. Together, the findings here indicated that GA could be considered as an effective therapeutic candidate against human gastric cancer progression in future.

Topics: Actins; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cisplatin; Epithelial-Mesenchymal Transition; Ginkgo biloba; Humans; Janus Kinase 2; Male; Matrix Metalloproteinases; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Reactive Oxygen Species; rho-Associated Kinases; Salicylates; Signal Transduction; STAT3 Transcription Factor; Stomach Neoplasms