Rg3 inhibits hypoxia-induced tumor exosomes from boosting pancreatic cancer vasculogenic mimicry through the HIF-1α/LARS1/mTOR axis

Abstract

Background: Pancreatic cancer (PC), characterized by a poor prognosis, can utilize hypoxia to activate vasculogenic mimicry (VM) and facilitate metastasis. Exosomes serve as crucial mediators in this hypoxic environment. Our previous studies demonstrated that Rg3 could counteract VM by modulating the impact of PC-derived exosomes.

Aim: This study focuses on the carcinogenic mechanism of PC in a hypoxic environment.

Methods: Exosomes from PANC-1 and BxPC-3 cells under normoxic or hypoxic conditions were isolated and characterized by western blot (WB) and nanoparticle trafficking analysis. These PC cells' VM potential was assessed through tube formation and WB. Molecular mechanisms were explored using proteomics analysis, bioinformatics analysis, and the gain- and loss-of-function studies, and the efficacy of Rg3 targeting these exosomes was examined in vitro and in vivo.

Results: Exosomes from PANC-1 and BxPC-3 cells enhanced VM formation in PC cells under hypoxic conditions. Proteomics analysis revealed that these exosomes involved the HIF-1α/LARS1/mTOR axis. Hypoxia-activated HIF-1α led to high expression of LARS1 in PC cell exosomes, which were uptaken by recipient PC cells activating the mTOR signaling and promoting VM formation. Interaction between HIF-1α and LARS1 was further confirmed. In vitro and in vivo experiments demonstrated that Rg3 can diminish VM formation of PC cells triggered by the LARS1/mTOR axis in PC-derived exosomes under hypoxic conditions, improving the therapeutic effect of Rg3.

Conclusions: Our findings revealed a novel mechanism through which Rg3 inhibits VM in PC by modulating hypoxia-induced tumor exosomes, offering novel experimental insights for PC treatment.

Keywords: Exosomes; Hypoxia; LARS1/mTOR; Pancreatic cancer; Rg3; VM.