Galectin-3 supports stemness in ovarian cancer stem cells by activation of the Notch1 intracellular domain

• DOI: 10.18632/oncotarget.11920
• Publication Date: 2016-09-09T17:41:45Z
• Authors: Hyeok Gu Kang; Da-Hyun Kim; Seok-Jun Kim; Yunhee Cho; Junghyun Jung; Wonhee Jang; Kyung-Hee Chun
• Keywords: cancer stem cells; Notch1/metabolism*; Galectin 3; Nude; Apoptosis; Mice; Ovarian Neoplasms/pathology; Cell Movement; Apoptosis/genetics; Receptor, Notch1; Galectin 3/genetics; Ovarian Neoplasms; Heterologous; 0303 health sciences; Tumor; Blood Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; ovarian cancer; Neoplastic Stem Cells; Female; RNA Interference; Receptor; Research Paper; Neoplastic Stem Cells/metabolism*; Galectins; Cellular/metabolism; Transplantation, Heterologous; 610; Mice, Nude; Ovarian Neoplasms/metabolism*; Cell Line; Cell Proliferation/genetics; Ovarian Neoplasms/genetics; 03 medical and health sciences; Cell Line, Tumor; Spheroids, Cellular; galectin-3; Cell Movement/genetics; Animals; Humans; Galectin 3/metabolism*; Cell Proliferation; Neoplastic; Transplantation; Notch1; Notch1/genetics; Gene Expression Regulation; Spheroids

Ovarian cancer is the most lethal gynecologic disease because usually, it is lately sensed, easily acquires chemoresistance, and has a high recurrence rate. Recent studies suggest that ovarian cancer stem cells (CSCs) are involved in these malignancies. Here, we demonstrated that galectin-3 maintains ovarian CSCs by activating the Notch1 intracellular domain (NICD1). The number and size of ovarian CSCs decreased in the absence of galectin-3, and overexpression of galectin-3 increased them. Overexpression of galectin-3 increased the resistance for cisplatin and paclitaxel-induced cell death. Silencing of galectin-3 decreased the migration and invasion of ovarian cancer cells, and overexpression of galectin-3 reversed these effects. The Notch signaling pathway was strongly activated by galectin-3 overexpression in A2780 cells. Silencing of galectin-3 reduced the levels of cleaved NICD1 and expression of the Notch target genes, Hes1 and Hey1. Overexpression of galectin-3 induced NICD1 cleavage and increased expression of Hes1 and Hey1. Moreover, overexpression of galectin-3 increased the nuclear translocation of NICD1. Interestingly, the carbohydrate recognition domain of galectin-3 interacted with NICD1. Overexpression of galectin-3 increased tumor burden in A2780 ovarian cancer xenografted mice. Increased expression of galectin-3 was detected in advanced stages, compared to stage 1 or 2 in ovarian cancer patients, suggesting that galectin-3 supports stemness of these cells. Based on these results, we suggest that targeting galectin-3 may be a potent approach for improving ovarian cancer therapy.