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Induction of insulin production in rat pancreatic acinar carcinoma cells by conophylline.
- Source :
-
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2003 Oct; Vol. 57 (8), pp. 341-50. - Publication Year :
- 2003
-
Abstract
- 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 beta-cell inducers among various signal transduction inhibitors. As a result, a vinca alkaloid, conophylline, induced neurite formation at 0.1 approximately 0.3 microg/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.
- Subjects :
- Animals
Carcinoma, Acinar Cell metabolism
Carcinoma, Acinar Cell pathology
Cell Line, Tumor
Cell Survival drug effects
Homeobox Protein Nkx-2.2
Islets of Langerhans metabolism
Islets of Langerhans pathology
Mitogen-Activated Protein Kinases metabolism
Pancreatic Neoplasms metabolism
Pancreatic Neoplasms pathology
Rats
Reverse Transcriptase Polymerase Chain Reaction
Structure-Activity Relationship
Transcription Factors biosynthesis
Vinca Alkaloids chemistry
p38 Mitogen-Activated Protein Kinases
Cell Differentiation drug effects
Insulin biosynthesis
Islets of Langerhans drug effects
Vinca Alkaloids pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0753-3322
- Volume :
- 57
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
- Publication Type :
- Academic Journal
- Accession number :
- 14568228
- Full Text :
- https://doi.org/10.1016/s0753-3322(03)00096-9