Galectin-3 supports stemness in ovarian cancer stem cells by activation of the Notch1 intracellular domain.
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.
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
Hyeok Gu
HG
Kang
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
Da-Hyun
DH
Kim
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
Seok-Jun
SJ
Kim
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
Yunhee
Y
Cho
Department of Life Science, Dongguk University, Seoul, Republic of Korea.
Junghyun
J
Jung
Department of Life Science, Dongguk University, Seoul, Republic of Korea.
Wonhee
W
Jang
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
Kyung-Hee
KH
Chun
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001798:Blood Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D037161:Galectins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000378:metabolism; D014183:Transplantation, Heterologous
D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C428445:LGALS3 protein, human; D051881:Receptor, Notch1
Notch1; cancer stem cells; galectin-3; ovarian cancer