title: 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: Department of Obstetrics and Gynecology, Tokai University School of Medicine.
authors: Makiko
authors: M
authors: Harasawa
authors: Masanori
authors: M
authors: Yasuda
authors: Takeshi
authors: T
authors: Hirasawa
authors: Masaki
authors: M
authors: Miyazawa
authors: Masako
authors: M
authors: Shida
authors: Toshinari
authors: T
authors: Muramatsu
authors: Kensho
authors: K
authors: Douguchi
authors: Naruaki
authors: N
authors: Matsui
authors: Susumu
authors: S
authors: Takekoshi
authors: Hiroshi
authors: H
authors: Kajiwara
authors: R
authors: R
authors: Yoshiyuki Osamura
authors: Mikio
authors: M
authors: Mikami
references: Blood. 2006 Jan 1;107(1):285-92
references: 16141350
references: Mol Cancer Ther. 2006 May;5(5):1183-9
references: 16731750
references: J Clin Oncol. 2009 Jun 1;27(16):2630-7
references: 19380449
references: Int J Gynecol Cancer. 2006 Jan-Feb;16 Suppl 1:405-12
references: 16515634
references: Nat Med. 2002 Feb;8(2):128-35
references: 11821896
references: Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12574-8
references: 7809080
references: Transplantation. 1997 Jul 15;64(1):36-42
references: 9233698
references: J Hematol Oncol. 2009 Oct 27;2:45
references: 19860903
references: Biochem Biophys Res Commun. 2010 Apr 9;394(3):600-5
references: 20214883
references: Nat Genet. 1994 May;7(1):85-90
references: 7915601
references: Expert Rev Anticancer Ther. 2008 Jan;8(1):63-73
references: 18095884
references: Clin Cancer Res. 2008 Aug 15;14(16):5124-30
references: 18698030
references: Pathol Int. 2009 Jan;59(1):19-27
references: 19121088
references: Cell. 2005 Mar 25;120(6):747-59
references: 15797377
references: Science. 1996 Jul 12;273(5272):239-42
references: 8662507
references: Biochem Biophys Res Commun. 2004 Jan 9;313(2):443-6
references: 14684182
references: Acta Histochem Cytochem. 2010 May 1;43(2):33-44
references: 20514290
references: Proc Natl Acad Sci U S A. 1995 May 23;92(11):4947-51
references: 7539137
references: Urol Clin North Am. 2003 Aug;30(3):437-54, vii
references: 12953747
references: Acta Histochem Cytochem. 2007 Dec 18;40(5):139-42
references: 18224245
references: Nat Rev Cancer. 2004 May;4(5):335-48
references: 15122205
references: Hum Pathol. 2007 Sep;38(9):1310-20
references: 17555795
references: Lancet. 2008 Aug 9;372(9637):449-56
references: 18653228
references: J Clin Oncol. 2010 Apr 10;28(11):1904-10
references: 20231677
references: Mol Cell Biol. 2002 Oct;22(20):7004-14
references: 12242281
references: Hum Pathol. 2009 Jun;40(6):795-806
references: 19157506
references: Blood. 2002 Nov 15;100(10):3767-75
references: 12393646
references: Obstet Gynecol. 2002 Aug;100(2):281-7
references: 12151151