Tumor Biology

, Volume 37, Issue 1, pp 1327–1336 | Cite as

The anti-ovarian cancer activity by WYE-132, a mTORC1/2 dual inhibitor

  • Dan Zhang
  • Hexia Xia
  • Wei Zhang
  • Bo Fang
Original Article


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.


Epithelial ovarian cancer WYE-132 mTORC1/2 Apoptosis Taxol sensitization and SphK1 



This work was supported by the National Natural Science Foundation.

Conflicts of interest

The authors have no conflict of interests.


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyRuijin Hospital affiliated to Shanghai Jiaotong UniversityShanghaiChina
  2. 2.Obstetrics and Gynecology HospitalFudan UniversityShanghaiChina
  3. 3.Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghaiChina

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