BACKGROUND/AIM: Epidemiological studies have demonstrated that type 2 diabetes mellitus (T2DM) is a risk factor for pancreatic ductal adenocarcinoma (PDAC); however, the underlying mechanisms remain unclear. Recent studies have suggested a potential link between proinsulin, a prohormone of insulin, and cancer. In this study, we examined the tumorigenic effects of proinsulin in PDAC. MATERIALS AND METHODS: We measured the expression levels of the insulin receptor (IR) gene isoforms IR-A and IR-B in tumor samples from 5 patients with PDAC and in the human PANC-1 pancreatic adenocarcinoma cell line using reverse transcription-PCR. We then assessed the effect of proinsulin treatment on ERK and AKT phosphorylation in PANC-1 cells using western blotting. We also evaluated the effect of proinsulin treatment on cell proliferation, resistance to an anti-cancer drugs, and cell invasion using direct cell counting and a WST-1 assay, an annexin/propidium iodine cell death detection assay, and an invasion assay, respectively. Finally, we used RNA sequencing and quantitative reverse transcription-PCR to identify genes whose expression was altered by proinsulin treatment. RESULTS: IR-A was expressed in tumor tissues from four out of five PDAC patients and in PANC-1 cells. Proinsulin stimulation significantly increased ERK1/2 phosphorylation in PANC-1 cells and also increased AKT phosphorylation, albeit to a lesser extent. Proinsulin stimulation significantly induced cell proliferation, protected against staurosporine-induced apoptosis, and promoted PANC-1 cell invasion. Consistent with these results, proinsulin stimulation upregulated the expression of genes related to cell proliferation, anti-cancer drug resistance, and cell invasion in PANC-1 cells. CONCLUSION: Proinsulin may promote PDAC tumor development by binding to IR-A and activating the ERK pathway.
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Tomonori Tsuyama
Hanchen Dong
Takenari Sato
Kumamoto University
Kumamoto Health Science University
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Tsuyama et al. (Fri,) studied this question.
www.synapsesocial.com/papers/69f44325967e944ac55667d3 — DOI: https://doi.org/10.21873/anticanres.18130