Analysis of hypoxia-inducible factors in ovarian tumors focusing on individual-based treatment

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Everolimus(a derivative of rapamycin)-treated cells and non-treated cells were found not to 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-1αdegradation 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-1αby VHL and induction of apoptosis by cleaved caspase-3.