Corosolic acid delivered by exosomes from Eriobotrya japonica decreased pancreatic cancer cell proliferation and invasion by inducing SAT1-mediated ferroptosis

Abstract

Background: In this study, we investigated whether Exo regulate the proliferation and invasion of PC.

Methods: In this study, we isolated the Eriobotrya japonica Exo using Ultra-high speed centrifugal method. Mass spectrum were used for Exo active components analysis. PC (Capan-1 and Bxpc-3) cells proliferation, migration, and apoptosis were detected using CCK8, ethynyldeoxyuridine, transwell, wound healing, and flow cytometry analyses. We also constructed a lung metastatic mouse model and subcutaneous tumor model to illustrate the regulation effect of Exo or active components. Proteomics were used to reveal the regulatory mechanism responsible for the observed effects.

Results: We isolated Eriobotrya japonica Exo and found that Exo treatment significantly suppressed cell migration and proliferation in both in vivo and in vitro using Capan-1. Mass spectrum for Exo active components analysis found that Exo contains high amounts of corosolic acid (CRA). The further study found that CRA treatment inhibit the proliferation, migration, and increased cell death of both Capan-1 and Bxpc-3 cells in a concentration-dependent manner. In vivo experiments confirmed that CRA inhibited pulmonary metastasis by decreasing the number of metastatic foci. Cell proteomics analysis showed that CRA treatment induced spermidine/spermine N1-acetyltransferase 1 (SAT1)-dependent ferroptosis. Treatment with the ferroptosis suppressor ferrostatin-1 significantly reversed CRA-induced cell apoptosis.

Conclusion: The data suggested that corosolic acid delivered by exosomes from Eriobotrya japonica decreased pancreatic cancer cell proliferation and invasion by inducing SAT1-mediated ferroptosis.

Keywords: Corosolic acid; Eriobotrya japonica Exosome; Ferroptosis; Oxidative stress; Pancreatic cancer; SAT1.