Analysis of mTOR inhibition-involved pathway in ovarian clear cell adenocarcinoma.

Abstract

This study was designed to clarify the mechanism of the mammalian target of rapamycin (mTOR)-hypoxia inducible factor-1 (HIF-1) pathway using the cultured cell strain derived from human ovarian clear cell adenocarcinoma (CCA). Everolimus (a derivative of rapamycin)-treated cells and non-treated cells did not show any difference in mTOR expression. But, phosphorylated-mTOR (p-mTOR) expression significantly decreased in the treated cells, and mTOR-related factors such as phosphorylated-4E-BP1 (p-4E-BP1), HIF-1α, and vascular endothelial growth factor (VEGF) in the downstream region of mTOR revealed a marked decrease in expression. The analysis of influences of the drug on the HIF-1α degradation system showed an increase in von-Hippel Lindau (VHL) expression in the treated cells. Increase of cleaved caspase-3, one of key factors involved in apoptosis, was also shown in the treated cells. In the next step, using nude mice implanted with RMG-1 cells, a decrease in tumor size was demonstrated in 4 of the 7 mice which were orally administered with everolimus. As a result, it was suggested that everolimus administration would be helpful as an anti-tumor therapy for CCA not only via down-regulation of p-mTOR but also degradation of HIF-1α by VHL and induction of apoptosis by cleaved caspase-3.

• Authors: Makiko Harasawa, Masanori Yasuda, Takeshi Hirasawa, Masaki Miyazawa, Masako Shida, Toshinari Muramatsu, Kensho Douguchi, Naruaki Matsui, Susumu Takekoshi, Hiroshi Kajiwara, R Yoshiyuki Osamura, Mikio Mikami
• Journal: Acta histochemica et cytochemica (Acta Histochem Cytochem) Vol. 44 Issue 2 Pg. 113-8 (Apr 28 2011) ISSN: 1347-5800 [Electronic] Japan
• PMID: 21614172 (Publication Type: Journal Article)