Ginkgoic acid impedes gastric cancer cell proliferation, migration and EMT through inhibiting the SUMOylation of IGF-1R.

Abstract

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.

• Authors: Dongtao Liu, Zubin Li, Zhijuan Yang, Junwen Ma, Saihu Mai
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 337 Pg. 109394 (Mar 01 2021) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 33508304 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• IGF1R protein, human
• RNA, Small Interfering
• SNAI2 protein, human
• SUMO-1 Protein
• SUMO1 protein, human
• SUMO2 protein, human
• Salicylates
• Small Ubiquitin-Related Modifier Proteins
• Snail Family Transcription Factors
• ginkgolic acid
• Receptor, IGF Type 1

Topics

• Animals
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Mice
• Mice, Nude
• RNA Interference
• RNA, Small Interfering (metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, genetics, metabolism)
• SUMO-1 Protein (antagonists & inhibitors, genetics, metabolism)
• Salicylates (pharmacology, therapeutic use)
• Small Ubiquitin-Related Modifier Proteins (antagonists & inhibitors, genetics, metabolism)
• Snail Family Transcription Factors (genetics, metabolism)
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Sumoylation (drug effects)
• Transplantation, Heterologous