Galectin-3 Inhibits Osteoblast Differentiation through Notch Signaling

• Published in: Neoplasia (New York, N.Y.) Vol. 16; no. 11; pp. 939 - 949
• Main Authors: Nakajima, Kosei, Kho, Dhong Hyo, Yanagawa, Takashi, Harazono, Yosuke, Gao, Xiaoge, Hogan, Victor, Raz, Avraham
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2014
• Subjects: Alkaline Phosphatase - genetics; Alkaline Phosphatase - metabolism; Calcium - metabolism; Cell Differentiation; Cell Line; Cell Line, Tumor; Coculture Techniques; Collagen Type I - genetics; Core Binding Factor Alpha 1 Subunit - genetics; Galectin 3 - genetics; Galectin 3 - metabolism; Gene Expression; HEK293 Cells; Humans; Integrin-Binding Sialoprotein - genetics; Microscopy, Confocal; Oncology; Osteoblasts - cytology; Osteoblasts - metabolism; Receptor, Notch1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; AA; hFOB; ascorbic acid; 1,25-(OH) 2D 3; ALP; β-glycerophosphate; carbohydrate recognition-binding domain; pNPP; β-GP; p-nitrophenol phosphate substrate; CRD; NICD; Notch intracellular domain; alkaline phosphatase; 1α-25-dihydroxycholecalciferol; human fetal osteoblast; 1,25-(OH)2D3
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2014.09.005

Abstract Patients with bone cancer metastasis suffer from unbearable pain and bone fractures due to bone remodeling. This is caused by tumor cells that disturb the bone microenvironment. Here, we have investigated the role of tumor-secreted sugar-binding protein, i.e., galectin-3, on osteoblast differentiation and report that it downregulates the expression of osteoblast differentiation markers, e.g., RUNX2 , SP7 , ALPL , COL1A1 , IBSP , and BGLAP , of treated human fetal osteoblast (hFOB) cells. Co-culturing of hFOB cells with human breast cancer BT-549 and prostate cancer LNCaP cells harboring galectin-3 has resulted in inhibition of osteoblast differentiation by the secreted galectin-3 into culture medium. The inhibitory effect of galectin-3 was found to be through its binding to Notch1 in a sugar-dependent manner that has led to accelerated Notch1 cleavage and activation of Notch signaling. Taken together, our findings show that soluble galectin-3 in the bone microenvironment niche regulates bone remodeling through Notch signaling, suggesting a novel bone metastasis therapeutic target.