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.