The anti-ovarian cancer activity by WYE-132, a mTORC1/2 dual inhibitor
- 143 Downloads
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.
KeywordsEpithelial 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.
- 24.Yao C, Wu S, Li D, Ding H, Wang Z, Yang Y, et al. Co-administration phenoxodiol with doxorubicin synergistically inhibit the activity of sphingosine kinase-1 (Sphk1), a potential oncogene of osteosarcoma, to suppress osteosarcoma cell growth both in vivo and in vitro. Mol Oncol. 2012;6:392–404.CrossRefPubMedGoogle Scholar
- 26.Aggarwal BB, Shishodia S, Takada Y, Banerjee S, Newman RA, Bueso-Ramos CE, et al. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res. 2005;11:7490–8.CrossRefPubMedGoogle Scholar
- 29.Tazuke SI, Mazure NM, Sugawara J, Carland G, Faessen GH, Suen LF, et al. Hypoxia stimulates insulin-like growth factor binding protein 1 (IGFBP-1) gene expression in HEPG2 cells: a possible model for IGFBP-1 expression in fetal hypoxia. Proc Natl Acad Sci U S A. 1998;95:10188–93.CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Pignata S, Scambia G, Katsaros D, Gallo C, Pujade-Lauraine E, De Placido S, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2014;15:396–405.CrossRefPubMedGoogle Scholar
- 40.Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase iii trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage iii ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2003;21:3194–200.CrossRefPubMedGoogle Scholar