We set up a screening system to detect low-molecular-weight compounds that induce insulin expression in pancreatic
acinar carcinoma AR42J
cells. They can differentiate into insulin-producing
cells with neuron-like morphological change when treated with activin A. We employed this morphological change for the screening of β-
cell inducers among various signal transduction inhibitors. As a result, a vinca alkaloid, conophylline, induced neurite formation at 0.1
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0.3 μg/ml in 72 h, like activin A. Conophylline-treated
cells were found to express insulin as measured at both mRNA and protein levels. By RT-PCR analysis, conophylline-treated
cells were shown to express neurogenin3 strongly. They also expressed Beta2/NeuroD and Nkx2.2, but not Pax4 and PP. Although activin A induces nuclear translocation of Smad2, conophylline did not. But the latter induced p38 activation, like activin A, as detected by phosphorylation. Pretreatment with a p38-specific inhibitor, SB203580, lowered the conophylline-induced insulin production. Therefore, p38 activation would be involved in the differentiation of AR42J
cells into insulin-producing
cells. Studies on structure–activity relationship with conophyllidine, conofoline, conophyllinine, and related monomer alkaloids showed that the dimeric aspidosperma structure with the dihydrofuran unit in its center was essential for the differentiation-inducing activity.