Tumor Cell Derived Exosomal GOT1 Suppresses Tumor Cell Ferroptosis to Accelerate Pancreatic Cancer Progression by Activating Nrf2/HO-1 Axis via Upregulating CCR2 Expression

Abstract

Recently, evidence has shown that GOT1 expression is upregulated in pancreatic cancer tissues and promotes cancer development, but the specific mechanism remains unclear. We found that GOT1 expression was upregulated in pancreatic cancer cell-derived exosomes. When PANC-1 cells were incubated with exosomes alone or transfected together with si-GOT1, we found that exosomes enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-GOT1 reversed the effects of exosomes. The results of online bioinformatics database analysis indicated that CCR2 was a potential binding protein of GOT1 and is highly expressed in pancreatic cancer tissues. PANC-1 cells were transfected with pcDNA-CCR2 or si-CCR2, and it was found that pcDNA-CCR2 enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-CCR2 had an opposite effect. Next, exosome-treated cells were transfected with si-GOT1 alone or together with pcDNA-CCR2, and we found that exosomes promoted CCR2 expression, promoted cell proliferation and invasion, and inhibited ferroptosis, the transfection of si-GOT1 abolished the effect of exosomes, and the transfection of pcDNA-CCR2 again reversed the effect of si-GOT1. Furthermore, when exosome-treated cells were transfected with si-GOT1 alone or co-incubated with Nrf2 activator NK-252, we found that si-GOT1 reversed the promoting effect of exosomes on Nrf2 and HO-1 expression, as well as its inhibitory effect on ferroptosis, but this effect was abrogated by NK-252. In vivo studies showed that knockdown of GOT1 expression inhibited tumor formation compared with tumor tissues formed upon exosome induction, which was mediated by promoting ferroptosis via suppressing the protein expression of GOT1, CCR2, Nrf2 and HO-1 in tumor tissues.

Exosomal HSPB1, interacting with FUS protein, suppresses hypoxia‐induced ferroptosis in pancreatic cancer by stabilizing Nrf2 mRNA and repressing P450

“…Except for overloaded Fe concentration, excessive lipid peroxidation is an outstanding feature of ferroptosis. Accordingly, Nrf2/HO‐1/GPX4 was regarded as one of the most concerned anti‐ferroptosis pathways in tumours and non‐cancerous tissues 45–47 . In this study, we reported that Nrf2/HO‐1 was activated by cancer cell‐derived exosomal HSPB1 in hypoxic pancreatic cancer cells via FUS protein, and knockdown of HSPB1 or FUS caused suppression of Nrf2/HO‐1, increased the level of the ferroptosis fuel P450 oxidases, 48,49 and inhibited pancreatic cancer progression in vitro and in vivo.…”

Ferroptosis: a promising candidate for exosome-mediated regulation in different diseases

“…In addition, Guo et al found that GOT1 protein enrichment in exosomes secreted by pancreatic cancer cells inhibits ferroptosis of cancer cells and promotes tumour development. In terms of mechanism, GOT1 can upregulate the expression of the C–C motif chemokine receptor-2 (CCR2), thereby activating the Nrf2/HO-1 axis to resist ferroptosis in cancer cells [ 79 ].…”

The engineered exosomes targeting ferroptosis: A novel approach to reverse immune checkpoint inhibitors resistance

“…The C–C motif chemokine receptor‐2 (CCR2) is reportedly highly expressed in cancer cells and correlated with poor prognosis 66 . It was shown that glutamic‐oxaloacetic transaminase 1 (GOT1) from tumor‐derived exosomes could upregulate CCR2 to stimulate the Nrf2‐HO‐1 pathway, resulting in increased GPX4 and decreased ROS, MDA, and Fe 2+ levels to hinder ferroptosis and eventually promoted tumor cell migration and invasion 67 . Therefore, targeting the exosome‐mediated Nrf2‐HO‐1 axis represents a potential approach to regulate ferroptosis in tumor cells.…”