Inhibitory effect of LiCl treatment on pancreatic islet β-cell tumorigenesis in the mouse model of multiple endocrine neoplasia type 1

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NIDDK	CANCER-18

Authors

• VI Parekh
• SS Desai
• SD Modali
• SK Agarwal

Abstract

Mouse models of human disease are a valuable resource for testing experimental therapeutic interventions. Mice heterozygous in the germline for the multiple endocrine neoplasia type 1 (MEN1) gene recapitulate the human MEN1 syndrome. Similar to human MEN1 patients, mice with germline heterozygous inactivation of Men1 develop endocrine tumors of the parathyroids, pituitary, and pancreas. After 9 months, Men1+/- mice develop pancreatic islet hyperplasia (a pre-tumor stage), followed by islet β-cell tumor (insulinoma) development after 12 months. We have shown that the β-cell differentiation factor HLXB9 was phosphorylated by GSK-3β, and insulimonas had increased levels of GSK-3β and phospho-HLXB9. Furthermore, in 3 different rodent insulinoma cell lines, GSK-3β inhibition by LiCl significantly reduced cell proliferation and induced apoptosis. Therefore, we examined the effect of in vivo LiCl treatment on pancreatic islets in the mouse model of MEN1. TUNEL-positive cells (apoptosis) were observed in 9 hyperplastic islets of LiCl-treated Men1+/- mice (n=5, age 12 months), and not in PBS-treated Men1+/- mice. These results indicate that LiCl could induce islet β-cell apoptosis by inhibiting a tumorigenic pathway activated upon Men1 loss. Further studies in this mouse model are warranted to elucidate whether LiCl treatment affects the development of other MEN1-associated tumors.

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