title: The anti-ovarian cancer activity by WYE-132, a mTORC1/2 dual inhibitor.
abstract: Epithelial ovarian cancer is the most common and lethal gynecological cancer in USA and around the world, causing major mortality annually. In the current study, we investigated the potential anti-ovarian cancer activity of WYE-132, a mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor. Our results showed that WYE-132 potently inhibited proliferation of primary and established human ovarian cancer cells. Meanwhile, WYE-132 induced caspase-dependent apoptosis in ovarian cancer cells. At the molecular level, WYE-132 blocked mTORC1/2 activation and inhibited expression of mTOR-regulated genes (cyclin D1 and hypoxia-inducible factor 1α). Interestingly, introducing a constitutively active AKT (caAKT), which restored mTORC1/2 activation in WYE-132-treated ovarian cancer cells, only mitigated (but not abolished) WYE-132-mediated growth inhibition and apoptosis. Further studies showed that WYE-132 inhibited sphingosine kinase-1 (SphK1) activity, leading to pro-apoptotic ceramide production in ovarian cancer cells. Meanwhile, WYE-132-induced cytotoxicity against ovarian cancer cells was inhibited by sphingosine-1-phosphate (S1P) but was aggravated by SphK1 inhibitor SKI-II or C6 ceramide. In vivo, WYE-132 inhibited ovarian cancer cell growth, and its activity was further enhanced when co-administrated with paclitaxel (Taxol). These results demonstrate that WYE-132 inhibits ovarian cancer cell proliferation through mTOR-dependent and mTOR-independent mechanisms and indicate a potential value of WYE-132 in ovarian cancer treatment.
authors: Department of Obstetrics and Gynecology, Ruijin Hospital affiliated to Shanghai Jiaotong University, Shanghai, China.|Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
authors: Dan
authors: D
authors: Zhang
authors: Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
authors: Hexia
authors: H
authors: Xia
authors: Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
authors: Wei
authors: W
authors: Zhang
authors: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China. bo_fangzhongshan@163.com.
authors: Bo
authors: B
authors: Fang
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage; D010671:Phenylurea Compounds / Q000737:chemistry*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000099157:Sphingosine Kinase
chemical_list: D053148:Caspase 3; D019938:Cyclin D1; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D017239:Paclitaxel; D010671:Phenylurea Compounds; D017853:Phosphotransferases (Alcohol Group Acceptor); D011720:Pyrazoles; D058570:TOR Serine-Threonine Kinases; D000099157:Sphingosine Kinase; C530104:CCND1 protein, human; C497442:HIF1A protein, human; C547581:WYE 125132; C505407:CASP3 protein, human
keywords: Apoptosis; Epithelial ovarian cancer; Taxol sensitization and SphK1; WYE-132; mTORC1/2