1α,25(OH)2D3 Analog, MART-10, Inhibits Neuroendocrine Tumor Cell Metastasis After VEGF-A Stimulation

Abstract

Aims: Pancreatic neuroendocrine tumors (PanNETs) are usually diagnosed in an advanced stage. Most patients with PanNETs die of metastasis. Vascular endothelial growth factor-A (VEGF-A) is a strong stimulator of angiogenesis and tumor metastasis. We aimed to investigate the effect of MART-10 [19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃], a 1α,25-dihydroxy-vitamin D3 (1α,25(OH)₂D₃) analog, on PanNET cell metastasis after VEGF-A stimulation.

Materials and methods: Migration and invasion assays, western blot, and immunofluorescent staining were applied in this study.

Results: VEGF-A increased PanNET cell migration and invasion, which was attenuated by 1α,25(OH)₂D₃ and MART-10. VEGF-A treatment stimulated epithelial-mesenchymal transition (EMT) of PanNET cells. During this process, expression of snail family transcriptional repressor 1 and 2, and fibronectin was up-regulated. 1α,25(OH)₂D₃ and MART-10 counteracted VEGF-A-induced EMT. In addition, expression of neuropilin 1, a key protein in VEGF-A signaling, was down-regulated by 1α,25(OH)₂D₃ and MART-10. Furthermore, synthesis of F-actin was increased by VEGF-A and reduced by 1α,25(OH)₂D₃ and MART-10.

Conclusion: Our data indicate that MART-10 could be deemed a promising drug for PanNET treatment.

Keywords: 1α,25(OH)2D3; EMT; MART-10; PanNET; VEGF-A; metastasis; vitamin D.