Effect of EGR1-mediated glutamine metabolic reprogramming through mTOR signaling pathway on pancreatic stellate cell activation and pancreatic cancer liver metastasis.

Abstract

e16359 Background: Pancreatic cancer is one of the most malignant cancers with an occult presentation and difficult diagnosis. Liver metastasis, which accounts for 90% of metastatic pancreatic cancer, is particularly associated with poor prognosis and high mortality. Glutamine metabolic reprogramming is a major source of energy for metastatic cancer cells. However, whether it is involved in the crosstalk between pancreatic stellate cells (PSCs) and cancer cells and cancer metastasis remains unclear. Methods: In this study, Pan02 cell lines and C57 / BL6 mouse PSCs were used to investigate the function of upstream transcription factors, glutamate ammonia ligase (GLUL) and early growth response gene 1 (EGR1), on PSC activation and tumour metastasis. Results: ELISA and Western blot showed that GLUL promoted glutamine synthesis and secretion in PSCs and inhibited mTOR-mediated activation of PSCs through EGR1. When co-cultured with EGR1/GLUL-overexpressed PSCs, Pan02 cells exhibited metabolic reprogramming manifested by suppressed autophagy levels and vasculogenesis, resulting in insufficient energy intake. The crosstalk between PSCs and pancreatic cancer cells reduced the proliferation, migration and invasion of pancreatic cancer cells and ultimately inhibited pancreatic cancer liver metastasis. Conclusions: Our results indicate that EGR1-mediated glutamine metabolic reprogramming is involved in the interaction of PSCs and pancreatic cancer cells and inhibits pancreatic cancer liver metastasis. In the future, EGR1 may be the potential drug target and better treatment for liver metastatic pancreatic cancer.