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

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Tumor Biology

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.

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Acknowledgments

This work was supported by the National Natural Science Foundation.

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The authors have no conflict of interests.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Ruijin Hospital affiliated to Shanghai Jiaotong University, Shanghai, China

    Dan Zhang

  2. Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China

    Dan Zhang, Hexia Xia & Wei Zhang

  3. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Bo Fang

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  1. Dan Zhang
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  2. Hexia Xia
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  3. Wei Zhang
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Correspondence to Bo Fang.

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Zhang, D., Xia, H., Zhang, W. et al. The anti-ovarian cancer activity by WYE-132, a mTORC1/2 dual inhibitor. Tumor Biol. 37, 1327–1336 (2016). https://doi.org/10.1007/s13277-015-3922-0

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  • DOI: https://doi.org/10.1007/s13277-015-3922-0

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