Islet Amyloid Polypeptide Does Not Suppress Pancreatic Cancer

Overview

Journal Mol Metab

Specialty Cell Biology

Date 2023 Jan 9

PMID 36621763

Authors

Austin J Taylor

Evgeniy Panzhinskiy

Paul C Orban

Francis C Lynn

David F Schaeffer

James D Johnson

Janel L Kopp

C Bruce Verchere

Affiliations

Soon will be listed here.

Abstract

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; Trp53; Ptf1a) 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; Trp53; Ptf1a 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.

Citing Articles

Select Endocrine Disorders and Exosomes in Early PDAC Diagnosis.

Wlodarczyk B, Durko L, Walczak K, Talar-Wojnarowska R, Malecka-Wojciesko E Int J Mol Sci. 2024; 25(22).

PMID: 39596226 PMC: 11594802. DOI: 10.3390/ijms252212159.

References

Stevens R, Roddam A, Beral V . Pancreatic cancer in type 1 and young-onset diabetes: systematic review and meta-analysis. Br J Cancer. 2007; 96(3):507-9. PMC: 2360024. DOI: 10.1038/sj.bjc.6603571. View

Hay D, Christopoulos G, Christopoulos A, Poyner D, Sexton P . Pharmacological discrimination of calcitonin receptor: receptor activity-modifying protein complexes. Mol Pharmacol. 2005; 67(5):1655-65. DOI: 10.1124/mol.104.008615. View

Venkatanarayan A, Raulji P, Norton W, Flores E . Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73. Cell Cycle. 2015; 15(2):164-71. PMC: 4825839. DOI: 10.1080/15384101.2015.1121333. View

Raleigh D, Zhang X, Hastoy B, Clark A . The β-cell assassin: IAPP cytotoxicity. J Mol Endocrinol. 2017; 59(3):R121-R140. DOI: 10.1530/JME-17-0105. View

Magkos F, Fabbrini E, Patterson B, Eagon J, Klein S . Portal vein and systemic adiponectin concentrations are closely linked with hepatic glucose and lipoprotein kinetics in extremely obese subjects. Metabolism. 2011; 60(11):1641-8. PMC: 3166552. DOI: 10.1016/j.metabol.2011.03.019. View

Ramachandran V, Arumugam T, Hwang R, Greenson J, Simeone D, Logsdon C . Adrenomedullin is expressed in pancreatic cancer and stimulates cell proliferation and invasion in an autocrine manner via the adrenomedullin receptor, ADMR. Cancer Res. 2007; 67(6):2666-75. DOI: 10.1158/0008-5472.CAN-06-3362. View

Jackson E, Willis N, Mercer K, Bronson R, Crowley D, Montoya R . Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 2001; 15(24):3243-8. PMC: 312845. DOI: 10.1101/gad.943001. View

Nakamura M, Han B, Nishishita T, Bai Y, Kakudo K . Calcitonin targets extracellular signal-regulated kinase signaling pathway in human cancers. J Mol Endocrinol. 2007; 39(6):375-84. DOI: 10.1677/JME-07-0036. View

Janson J, Ashley R, Harrison D, McIntyre S, Butler P . The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes. 1999; 48(3):491-8. DOI: 10.2337/diabetes.48.3.491. View

10.

Mack C, Soares C, Wilson J, Athanacio J, Turek V, Trevaskis J . Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight. Int J Obes (Lond). 2009; 34(2):385-95. DOI: 10.1038/ijo.2009.238. View

11.

Insel P, Zhang L, Murray F, Yokouchi H, Zambon A . Cyclic AMP is both a pro-apoptotic and anti-apoptotic second messenger. Acta Physiol (Oxf). 2011; 204(2):277-87. PMC: 3125423. DOI: 10.1111/j.1748-1716.2011.02273.x. View

12.

Dacquin R, Davey R, Laplace C, Levasseur R, Morris H, Goldring S . Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo. J Cell Biol. 2004; 164(4):509-14. PMC: 2171986. DOI: 10.1083/jcb.200312135. View

13.

Buhlmann N, Leuthauser K, Muff R, Fischer J, Born W . A receptor activity modifying protein (RAMP)2-dependent adrenomedullin receptor is a calcitonin gene-related peptide receptor when coexpressed with human RAMP1. Endocrinology. 1999; 140(6):2883-90. DOI: 10.1210/endo.140.6.6783. View

14.

Preziosi G, Oben J, Fusai G . Obesity and pancreatic cancer. Surg Oncol. 2014; 23(2):61-71. DOI: 10.1016/j.suronc.2014.02.003. View

15.

Turek V, Trevaskis J, Levin B, Dunn-Meynell A, Irani B, Gu G . Mechanisms of amylin/leptin synergy in rodent models. Endocrinology. 2009; 151(1):143-52. DOI: 10.1210/en.2009-0546. View

16.

Gebre-Medhin S, Mulder H, Pekny M, Westermark G, Tornell J, Westermark P . Increased insulin secretion and glucose tolerance in mice lacking islet amyloid polypeptide (amylin). Biochem Biophys Res Commun. 1998; 250(2):271-7. DOI: 10.1006/bbrc.1998.9308. View

17.

Courtade J, Klimek-Abercrombie A, Chen Y, Patel N, Lu P, Speake C . Measurement of Pro-Islet Amyloid Polypeptide (1-48) in Diabetes and Islet Transplants. J Clin Endocrinol Metab. 2017; 102(7):2595-2603. DOI: 10.1210/jc.2016-2773. View

18.

Keleg S, Kayed H, Jiang X, Penzel R, Giese T, Buchler M . Adrenomedullin is induced by hypoxia and enhances pancreatic cancer cell invasion. Int J Cancer. 2007; 121(1):21-32. DOI: 10.1002/ijc.22596. View

19.

Gradiz R, Silva H, Carvalho L, Botelho M, Mota-Pinto A . MIA PaCa-2 and PANC-1 - pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors. Sci Rep. 2016; 6:21648. PMC: 4756684. DOI: 10.1038/srep21648. View

20.

Iyengar N, Gucalp A, Dannenberg A, Hudis C . Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation. J Clin Oncol. 2016; 34(35):4270-4276. PMC: 5562428. DOI: 10.1200/JCO.2016.67.4283. View