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.

Reduced phosphocholine and hyperpolarized lactate provide magnetic resonance biomarkers of PI3K/Akt/mTOR inhibition in glioblastoma

“…These results are consistent with previous studies demonstrating a decrease in the translation of HIF-1a following inhibition of the PI3K signaling cascade. 36,37 Our results are also consistent with previous reports of decreased HIF-1a levels in several cancer models following treatment with everolimus 38 or LY294002. 39 HIF-1 is known to regulate the expression of ChoKa 23 and several glycolytic enzymes, including LDHA.…”

Alterations of Hypoxia-Induced Factor Signaling Pathway Due to Mammalian Target of Rapamycin (mTOR) Suppression in Ovarian Clear Cell Adenocarcinoma: In Vivo and in Vitro Explorations for Clinical Trial

“…We previously analyzed the expression of cleaved caspase-3 among various apoptosisrelated factors, and our in vitro study showed no expression of cleaved caspase-3 in the untreated group. 23 Inhibition of mTOR is considered to have led to cell death and apoptosis. These results suggest that everolimus not only inhibits mTOR signaling but also promotes VHL expression and that everolimus exhibits antitumor activity through inhibition of HIF-1> expression.…”

“…These results suggest that everolimus not only inhibits mTOR signaling but also promotes VHL expression and that everolimus exhibits antitumor activity through inhibition of HIF-1> expression. 23 Further analysis of VHL expression could lead to the identification of a new mediator in the intracellular signaling system. The efficacy of everolimus has primarily been studied in patients with renal cell carcinoma.…”

Induction of β-Defensin Expression by <i>Porphyromonas gingivalis</i>-Infected Human Gingival Graft Transplanted in <i>nu/nu</i> Mouse Subdermis

“…In addition, experiments using animals sometimes show differences in the reaction between humans and animals. To solve these problems, immunodeficient nu/nu mice or scid/scid mice have been widely used as in vivo models with human characteristics because various human tissues, including oral mucosa, can be transplanted into these mice [8, 10, 22, 31]. In oral mucosa, transplanted grafts frequently show cystic formation [10].…”