Metformin induces apoptosis in pituitary-derived folliculostellate cells via the IL-6/ERK pathway

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PURPOSE: The aim of this study was to investigate the function and regulatory mechanism of Interleukin-6 (IL-6) in pituitary-derived folliculostellate (PDFS) cells and to explore the mechanism of metformin against PDFS cells growth through IL-6. METHODS: Immunohistochemical staining was conducted on clinical samples from non-functioning pituitary adenomas (NFPA) patients and normal individuals to assess IL-6 and Programmed Death-Ligand 1(PD-L1) expression. PDFS cells were treated with IL-6 to evaluate their effects on cell viability, proliferation, and migration through various assays. Similar assays were performed to assess the counteractive effects of metformin, focusing on the IL-6/ERK pathway and PD-L1 expression. Western blot analysis was utilized to examine apoptosis-related proteins, and Annexin V-FITC/PI double staining was used to detect cell apoptosis. It also involves assessing the effects of metformin treatment on tumor IL-6 and PD-L1 expression, tumor size, and potential toxic side effects in PDFS xenograft mice. RESULTS: Clinical samples showed increased IL-6 and PD-L1 expression in NFPA compared to normal pituitary tissues. IL-6 treatment significantly enhanced PDFS cell viability(Increased by 46% within 48 h), proliferation(Increased by 24% within 48 h), and migration(Increased by 19% within 48 h). Metformin treatment resulted in the downregulation of IL-6 expression and mitigated IL-6-induced effects on PDFS cells. Additionally, metformin-induced apoptosis and reduced tumor size in xenograft nude mice without observable toxic side effects. CONCLUSION: Metformin downregulates the expression of IL-6 in PDFS cells, inhibits the activation of the ERK pathway, thereby suppressing cell proliferation and PD-L1 expression, and induces cell apoptosis.

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