MART-10 represses cholangiocarcinoma cell growth and high vitamin D receptor expression indicates better prognosis for cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a devastating disease due to no effective treatments available. Since the non-mineral functions of vitamin D emerges, 1α,25(OH)2D3, the active form of vitamin D, has been applied in anti-cancer researches. In this study, we demonstrated that both the 1α,25(OH)2D3 analog, MART-10, and 1α,25(OH)2D3 possessed anti-growth effect on human CCA cells with MART-10 much more potent than 1α,25(OH)2D3. The growth inhibition of both drugs were mediated by induction of G0/G1 cell cycle arrest through upregulation of p27 and downregulation of CDK4, CDK6, and cyclin D3. Human neutrophil gelatinase associated lipocalin (NGAL) was found to be involved in 1α,25(OH)2D3 and MART-10 meditated growth inhibition for CCA as knockdown of NGAL decreased Ki-67 expression in SNU308 cells and rendered SNU308 cells less responsive to 1α,25(OH)2D3 and MART-10 treatment. Vitamin D receptor (VDR) knockdown partly abolished MART-10-induced inhibition of NGAL and cell growth in SNU308 cells. The xenograft animal study demonstrated MART-10 could effectively repressed CCA growth in vivo without inducing obvious side effects. The IHC examination of human CCA specimen for VDR revealed that higher VDR expression was linked with better prognosis. Collectively, our results suggest that MART-10 could be a promising regimen for CCA treatment.

Effects of Metformin and Vitamin D on Clinical Outcome in Cholangiocarcinoma Patients

“…Furthermore, when they treated CCA cell lines with high receptor expression with vitamin D, it inhibited cell growth in a dose-dependent manner. MART-10 is a newly synthesized 1α,25(OH) 2 D3 analog [32] with potent inhibition of cell growth that has been highlighted in CCA cell lines [33]. These preclinical data reinforce the role of vitamin D treatment in CCA.…”

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

“…1 μg/ml leupeptin, and 1% Triton X-100). The detailed procedures for western blot were described previously (11). The antibodies used in this experiment were monoclonal antibodies against snail family transcriptional repressor 1 (SNAI1; 1:1,000, #3879; Cell Signaling Technology, Danvers, MA, USA), SNAI2 (1:1000, #9585; Cell Signaling Technology), fibronectin (1:1,000, NBP1-91258; Novus Biological, Littleton, CO, USA), vascular endothelial growth factor receptor 2 (VEGFR2; 1:500, sc-6251, Santa Cruz Biotechnology, Dallas, TX, USA), and neuropilin 1 (1:1,000, #3725; Cell Signaling Technology).…”

“…Further Aring modification of 19-nor-1α,25(OH) 2 D 3 generates a series of analogs (8), including MART-10 [19-nor-2α-(3hydroxypropyl)-1α,25(OH) 2 D 3 ] (9). MART-10 has been shown to be more active than 1α,25(OH) 2 D 3 in tumor growth inhibition against cholangiocarcinoma and pancreatic cancer in vitro and in vivo without inducing hypercalcemia (10,11). MART-10 was furthermore shown to repress metastatic potential of cancer cells (12)(13)(14)(15).…”

Vitamin D in liver cancer: novel insights and future perspectives

“…VDR expression was also found in human cholangiocarcinoma (CCA) tissue specimens ( 41 - 43 ). As in HCC, the treatment with vitamin D and/or vitamin D analogs showed beneficial effects in CCA cell cultures and in vivo models of CCA ( 41 - 47 ). Vitamin D or its analogs significantly impaired proliferation ( 41 , 42 ) and induced apoptosis in cultured cells ( 44 ), suppressed cholangiocarcinogenesis ( 43 , 48 ) and significantly inhibited tumor growth and progression in murine models of CCA ( 43 , 44 , 47 ).…”

“…As in HCC, the treatment with vitamin D and/or vitamin D analogs showed beneficial effects in CCA cell cultures and in vivo models of CCA ( 41 - 47 ). Vitamin D or its analogs significantly impaired proliferation ( 41 , 42 ) and induced apoptosis in cultured cells ( 44 ), suppressed cholangiocarcinogenesis ( 43 , 48 ) and significantly inhibited tumor growth and progression in murine models of CCA ( 43 , 44 , 47 ). Several studies examined the mechanisms behind these effects, suggesting that vitamin D induces cell cycle arrest through regulation of cyclin D1 ( 44 , 45 ), cyclin D3 ( 47 ), p21 ( 44 ), and p27 expression ( 47 ).…”