Gene silencing of glypican-3 in clear cell carcinoma of the ovary renders it more sensitive to the apoptotic agent paclitaxel in vitro and in vivo.
Glypican-3 (GPC3) is a heparan sulfate proteoglycan that is bound to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor, and glypicans can regulate the activity of a wide variety of growth and survival factors. We report here that GPC3 was expressed in clear cell carcinoma of the ovary, and not in other carcinomas. To evaluate the phenotype and potential preclinical relevance, we generated an ovarian cancer cell line stably transfected with plasmids encompassing shRNA targeting GPC3. We show that the clear cell carcinoma cell line with silenced GPC3 expression (GPC3 [-]) was more sensitive to paclitaxel than GPC3 (+) cells. In addition, the GPC3 silencing induced sensitization to paclitaxel was associated with the activation of an apoptosis pathway, as shown by flow cytometry. Moreover, we investigated the effect of GPC3 on peritoneal metastases using nude mice. Peritoneal metastases caused by GPC3 (-) were more sensitive to paclitaxel than those caused by GPC3 (+) cells. These results indicate that increased GPC3 expression in a clear cell carcinoma cell line may play a protective role against apoptosis, and so the downregulation of GPC3 may be a potential target to increase sensitivity to paclitaxel-induced apoptosis in clear cell carcinoma.
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Tomokazu
T
Umezu
Kiyosumi
K
Shibata
Maiko
M
Shimaoka
Hiroaki
H
Kajiyama
Eiko
E
Yamamoto
Kazuhiko
K
Ino
Akihiro
A
Nawa
Takeshi
T
Senga
Fumitaka
F
Kikkawa
D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D045744:Cell Line, Tumor; D005260:Female; D020868:Gene Silencing; D053673:Glypicans / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*
D053673:Glypicans; D017239:Paclitaxel