Title: Galectin-3 supports stemness in ovarian cancer stem cells by activation of the Notch1 intracellular domain
Abstract: // Hyeok Gu Kang 1, 2 , Da-Hyun Kim 1, 2 , Seok-Jun Kim 1, 2 , Yunhee Cho 1, 2 , Junghyun Jung 3 , Wonhee Jang 3 , Kyung-Hee Chun 1, 2 1 Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea 2 Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea 3 Department of Life Science, Dongguk University, Seoul, Republic of Korea Correspondence to: Kyung-Hee Chun, email: [email protected] Keywords: galectin-3, cancer stem cells, Notch1, ovarian cancer Received: February 23, 2016 Accepted: September 02, 2016 Published: September 09, 2016 ABSTRACT 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.