Islet amyloid polypeptide does not suppress pancreatic cancer

• Main Authors: Austin J. Taylor (Author), Evgeniy Panzhinskiy (Author), Paul C. Orban (Author), Francis C. Lynn (Author), David F. Schaeffer (Author), James D. Johnson (Author), Janel L. Kopp (Author), C. Bruce Verchere (Author)
• Format: Book
• Published: Elsevier, 2023-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Objectives: Pancreatic cancer risk is elevated approximately two-fold in type 1 and type 2 diabetes. Islet amyloid polypeptide (IAPP) is an abundant beta-cell peptide hormone that declines with diabetes progression. IAPP has been reported to act as a tumour-suppressor in p53-deficient cancers capable of regressing tumour volumes. Given the decline of IAPP during diabetes development, we investigated the actions of IAPP in pancreatic ductal adenocarcinoma (PDAC; the most common form of pancreatic cancer) to determine if IAPP loss in diabetes may increase the risk of pancreatic cancer. Methods: PANC-1, MIA PaCa-2, and H1299 cells were treated with rodent IAPP, and the IAPP analogs pramlintide and davalintide, and assayed for changes in proliferation, death, and glycolysis. An IAPP-deficient mouse model of PDAC (Iapp−/−; Kras+/LSL-G12D; Trp53flox/flox; Ptf1a+/CreER) was generated for survival analysis. Results: IAPP did not impact glycolysis in MIA PaCa-2 cells, and did not impact cell death, proliferation, or glycolysis in PANC-1 cells or in H1299 cells, which were previously reported as IAPP-sensitive. Iapp deletion in Kras+/LSL-G12D; Trp53flox/flox; Ptf1a+/CreER mice had no effect on survival time to lethal tumour burden. Conclusions: In contrast to previous reports, we find that IAPP does not function as a tumour suppressor. This suggests that loss of IAPP signalling likely does not increase the risk of pancreatic cancer in individuals with diabetes.

Item Description

2212-8778
10.1016/j.molmet.2023.101667