Neuropeptide gastrin-releasing peptide induces PI3K/reactive oxygen species-dependent migration in lung adenocarcinoma cells

Abstract

Nerve fibers and neurotransmitters have increasingly been shown to have a role in tumor progression. Gastrin-releasing peptide is a neuropeptide linked to tumor aggressiveness, acting as an autocrine tumor growth factor by binding to its receptor, gastrin-releasing peptide receptor, expressed by many tumors. Although neuropeptides have been previously linked to tumor cell proliferation, more recent studies have uncovered roles for neuropeptides in chemotaxis and metastasis. Understanding the precise roles of such peptides in cancer is crucial to optimizing targeted therapy design. We have previously described that gastrin-releasing peptide acts directly as a chemotactic factor for neutrophils, dependent on PI3K, ERK, and p38. In this study, we investigated roles for gastrin-releasing peptide in lung adenocarcinoma. We asked if gastrin-releasing peptide would act as a proliferative and/or chemotactic stimulus for gastrin-releasing peptide receptor-expressing tumor cells. In A549 cells, a non-small cell lung carcinoma line, the treatment with gastrin-releasing peptide leads to activation of AKT and ERK1/2, and production of reactive oxygen species. Gastrin-releasing peptide induced migration of A549 cells, dependent on gastrin-releasing peptide receptor and PI3K, but not ERK. However, no proliferation was observed in these cells in response to gastrin-releasing peptide, and gastrin-releasing peptide did not promote resistance to treatment with a chemotherapy drug. Our results suggest that, similar to what happens in neutrophils, gastrin-releasing peptide is a migratory, rather than a proliferative, stimulus, for non-small cell lung carcinoma cells, indicating a putative role for gastrin-releasing peptide and gastrin-releasing peptide receptor in metastasis.

Keywords: Gastrin-releasing peptide; cancer; chemotaxis; gastrin-releasing peptide; gastrin-releasing peptide receptor; metastasis; neuropeptide; non–small cell lung carcinoma.