Tumor Biology

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

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

Original Article

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.

Keywords

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

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation.

Conflicts of interest

The authors have no conflict of interests.

References

  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Kipps E, Tan DS, Kaye SB. Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research. Nat Rev Cancer. 2013;13:273–82.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Vaughan S, Coward JI, Bast Jr RC, Berchuck A, Berek JS, Brenton JD, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011;11:719–25.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Li XH, Chen XJ, Ou WB, Zhang Q, Lv ZR, Zhan Y, et al. Knockdown of creatine kinase B inhibits ovarian cancer progression by decreasing glycolysis. Int J Biochem Cell Biol. 2013;45:979–86.CrossRefPubMedGoogle Scholar
  5. 5.
    Meng Q, Xia C, Fang J, Rojanasakul Y, Jiang BH. Role of Pi3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70s6K1 pathway. Cell Signal. 2006;18:2262–71.CrossRefPubMedGoogle Scholar
  6. 6.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.CrossRefPubMedGoogle Scholar
  7. 7.
    Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24:7455–64.CrossRefPubMedGoogle Scholar
  8. 8.
    Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005;9:59–71.CrossRefPubMedGoogle Scholar
  9. 9.
    Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9–22.CrossRefPubMedGoogle Scholar
  10. 10.
    Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–34.CrossRefPubMedGoogle Scholar
  11. 11.
    Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, Godwin AK, et al. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene. 2004;23:5853–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene. 2006;25:6436–46.CrossRefPubMedGoogle Scholar
  13. 13.
    Griner SE, Joshi JP, Nahta R. Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion. Biochem Pharmacol. 2013;85:46–58.CrossRefPubMedGoogle Scholar
  14. 14.
    Wu R, Hu TC, Rehemtulla A, Fearon ER, Cho KR. Preclinical testing of pi3K/AKT/mTOR signaling inhibitors in a mouse model of ovarian endometrioid adenocarcinoma. Clin Cancer Res. 2011;17:7359–72.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, et al. RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res. 2007;13:4261–70.CrossRefPubMedGoogle Scholar
  16. 16.
    Wolpin BM, Hezel AF, Abrams T, Blaszkowsky LS, Meyerhardt JA, Chan JA, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27:193–8.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Javle MM, Shroff RT, Xiong H, Varadhachary GA, Fogelman D, Reddy SA, et al. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer. 2010;10:368.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Garrido-Laguna I, Tan AC, Uson M, Angenendt M, Ma WW, Villaroel MC, et al. Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer. Br J Cancer. 2010;103:649–55.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Vilar E, Perez-Garcia J, Tabernero J. Pushing the envelope in the mTOR pathway: the second generation of inhibitors. Mol Cancer Ther. 2011;10:395–403.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Sun SY. mTOR kinase inhibitors as potential cancer therapeutic drugs. Cancer Lett. 2013;340:1–8.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Yu K, Shi C, Toral-Barza L, Lucas J, Shor B, Kim JE, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res. 2010;70:621–31.CrossRefPubMedGoogle Scholar
  22. 22.
    Yu K, Toral-Barza L. Biochemical and pharmacological inhibition of mTOR by rapamycin and an ATP-competitive mTOR inhibitor. Methods Mol Biol. 2012;821:15–28.CrossRefPubMedGoogle Scholar
  23. 23.
    Sun H, Yu T, Li J. Co-administration of perifosine with paclitaxel synergistically induces apoptosis in ovarian cancer cells: more than just AKT inhibition. Cancer Lett. 2011;310:118–28.CrossRefPubMedGoogle Scholar
  24. 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
  25. 25.
    Ji F, Mao L, Liu Y, Cao X, Xie Y, Wang S, et al. K6PC-5, a novel sphingosine kinase 1 (Sphk1) activator, alleviates dexamethasone-induced damages to osteoblasts through activating Sphk1-Akt signaling. Biochem Biophys Res Commun. 2015;458:568–75.CrossRefPubMedGoogle Scholar
  26. 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
  27. 27.
    Averous J, Fonseca BD, Proud CG. Regulation of Cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene. 2008;27:1106–13.CrossRefPubMedGoogle Scholar
  28. 28.
    Toschi A, Lee E, Gadir N, Ohh M, Foster DA. Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J Biol Chem. 2008;283:34495–9.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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
  30. 30.
    Shida D, Takabe K, Kapitonov D, Milstien S, Spiegel S. Targeting Sphk1 as a new strategy against cancer. Curr Drug Targets. 2008;9:662–73.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yang YL, Ji C, Cheng L, He L, Lu CC, Wang R, et al. Sphingosine kinase-1 inhibition sensitizes curcumin-induced growth inhibition and apoptosis in ovarian cancer cells. Cancer Sci. 2012;103:1538–45.CrossRefPubMedGoogle Scholar
  32. 32.
    Zhang H, Wang Q, Zhao Q, Di W. Mir-124 inhibits the migration and invasion of ovarian cancer cells by targeting Sphk1. J Ovarian Res. 2013;6:84.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Chiba Y, Takeuchi H, Sakai H, Misawa M. Ski-ii, an inhibitor of sphingosine kinase, ameliorates antigen-induced bronchial smooth muscle hyperresponsiveness, but not airway inflammation, in mice. J Pharmacol Sci. 2010;114:304–10.CrossRefPubMedGoogle Scholar
  34. 34.
    Masamha CP, Benbrook DM. Cyclin D1 degradation is sufficient to induce G1 cell cycle arrest despite constitutive expression of Cyclin E2 in ovarian cancer cells. Cancer Res. 2009;69:6565–72.CrossRefPubMedGoogle Scholar
  35. 35.
    Worsley SD, Ponder BA, Davies BR. Overexpression of Cyclin D1 in epithelial ovarian cancers. Gynecol Oncol. 1997;64:189–95.CrossRefPubMedGoogle Scholar
  36. 36.
    Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 2008;15:678–85.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Huo HZ, Zhou ZY, Wang B, Qin J, Liu WY, Gu Y. Dramatic suppression of colorectal cancer cell growth by the dual mTORC1 and mTORC2 inhibitor AZD-2014. Biochem Biophys Res Commun. 2014;443:406–12.CrossRefPubMedGoogle Scholar
  38. 38.
    Brunn GJ, Williams J, Sabers C, Wiederrecht G, Lawrence Jr JC, Abraham RT. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and ly294002. EMBO J. 1996;15:5256–67.PubMedPubMedCentralGoogle Scholar
  39. 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. 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
  41. 41.
    Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361:2099–106.CrossRefPubMedGoogle Scholar

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

Personalised recommendations