The glycosyltransferase GnT-III activates Notch signaling and drives stem cell expansion to promote the growth and invasion of ovarian cancer

Abstract

Glycosylation changes associated with cellular transformation can facilitate the growth and progression of tumors. Previously we discovered that the gene encoding the glycosyltransferase GnT-III is elevated in epithelial ovarian carcinomas (EOCs) and leads to the production of abnormal truncated-linked glycan structures instead of the typical bisected forms. In this study, we are interested in discovering how these abnormal glycans impact the growth and progression of ovarian cancer. We have discovered using stable shRNA gene suppression that GnT-III expression controls the expansion of side-population cells, also known as cancer stem cells. More specifically, we found that GnT-III expression regulates the levels and activation of the heavily glycosylated Notch receptor involved in normal and malignant development. Suppression of GnT-III in EOC cell lines and primary tumor-derived cells resulted in an inhibition of Notch signaling that was more potent than pharmacologic blockage of Notch activation via γ-secretase inhibition. The inhibition resulted from the redirection of the Notch receptor to the lysosome, a novel mechanism. These findings demonstrate a new role for bisecting glycosylation in the control of Notch transport and demonstrate the therapeutic potential of inhibiting GnT-III as a treatment for controlling EOC growth and recurrence.

Core fucosylation of copper transporter 1 plays a crucial role in cisplatin‐resistance of epithelial ovarian cancer by regulating drug uptake

“…Altered glycosylations contribute to the pathophysiological events during EOC progressions . In ovarian cancer, the mRNA expression and activity of the glycosyltransferase GnT‐III, the enzyme responsible for the addition of bisecting N‐linked glycans, were increased.…”

“…The forced expression of ST6Gal‐I, which catalyzes the addition of sialic acid to the termini of N‐linked glycans, confers resistance to cisplatin, whereas ST6Gal‐I knockdown conversely sensitizes cells to cisplatin . The elevated fucosylation was also detected by AAL staining in ovarian cancer . Taniguchi and co‐workers discovered that the mRNA levels and activity of FUT8 were increased in serous adenocarcinoma ovarian tissues compared with normal ovarian tissue .…”

“…Altered glycosylations contribute to the pathophysiological events during EOC progressions. 1,[5][6][7][8][9][10][11][12] In ovarian cancer, the mRNA expression and activity of the glycosyltransferase GnT-III, the enzyme responsible for the addition of bisecting N-linked glycans, were increased. The forced expression of ST6Gal-I, which catalyzes the addition of sialic acid to the termini of N-linked glycans, confers resistance to cisplatin, whereas ST6Gal-I knockdown conversely sensitizes cells to cisplatin.…”

“…The resistance to platinum drugs usually occurs during the ovarian tumor progressions, and the treatment for recurrent ovarian cancer is often difficult due to resistance to chemotherapeutic agents . Aberrant glycosylation is a universal feature of cancer malignancy and metastatic progress including EOC …”

“…4,5 Aberrant glycosylation is a universal feature of cancer malignancy and metastatic progress including EOC. 1,[5][6][7][8][9][10][11][12] . Recent studies have reported that core fucosylation could participate in the EOC progression.…”