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Inhibition of Hec1 as a novel approach for treatment of primary liver cancer

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Abstract

Purpose

Highly expressed in cancer protein 1 (Hec1) is an oncogene and a promising molecular target for novel anticancer drugs. The purpose of this study was to evaluate the potential of a Hec1 inhibitor, TAI-95, as a treatment for primary liver cancer.

Methods

In vitro and in vivo methods were used to test the activity of TAI-95. Gene expression analysis was used to evaluate clinical correlation of the target.

Results

In vitro growth inhibition results showed that TAI-95 has excellent potency on a wide range of primary liver cancer cell lines (hepatoblastoma or hepatocellular carcinoma) (GI50 30–70 nM), which was superior to sorafenib and other cytotoxic agents. TAI-95 was relatively inactive in non-cancerous cell lines (GI50 > 10 μM). TAI-95 disrupts the interaction between Hec1 and Nek2 and leads to degradation of Nek2, chromosomal misalignment, and apoptotic cell death. TAI-95 showed synergistic activity in selected cancer cell lines with doxorubicin, paclitaxel, and topotecan, but not with sorafenib. TAI-95 shows excellent potency in a Huh-7 xenograft mouse model when administered orally. Gene expression analysis of clinical samples demonstrated increased expression of Hec1/NDC80 and associated genes (Nek2, SMC1A, and SMC2) in 27 % of patients, highlighting the potential for using this therapeutic approach to target patients with high Hec1 expression.

Conclusion

Inhibition of Hec1 using small molecule approach may represent a promising novel approach for the treatment of primary liver cancers.

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Abbreviations

Hec1:

Highly expressed in cancer protein 1

HCC:

Hepatocellular carcinoma

GI50 :

Growth inhibition concentration

References

  1. Lin CP, Liu CR, Lee CN, Chan TS, Liu HE (2010) Targeting c-Myc as a novel approach for hepatocellular carcinoma. World J hepatol 2(1):16–20. doi:10.4254/wjh.v2.i1.16

    PubMed Central  PubMed  Google Scholar 

  2. Seinstra BA, Defreyne L, Lambert B, Lam MG, Verkooijen HM, van Erpecum KJ, van Hoek B, van Erkel AR, Coenraad MJ, Al Younis I, van Vlierberghe H, van den Bosch MA (2012) Transarterial RAdioembolization versus ChemoEmbolization for the treatment of hepatocellular carcinoma (TRACE): study protocol for a randomized controlled trial. Trials 13(1):144. doi:10.1186/1745-6215-13-144

    Article  PubMed Central  PubMed  Google Scholar 

  3. Zhu AX, Blaszkowsky LS, Ryan DP, Clark JW, Muzikansky A, Horgan K, Sheehan S, Hale KE, Enzinger PC, Bhargava P, Stuart K (2006) Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J clin oncol off J Am Soc Clin Oncol 24(12):1898–1903. doi:10.1200/JCO.2005.04.9130

    Article  CAS  Google Scholar 

  4. Sacco R, Bargellini I, Ginanni B, Bertini M, Faggioni L, Federici G, Romano A, Bertoni M, Metrangolo S, Altomare E, Parisi G, Tumino E, Scaramuzzino A, Bresci G, Bartolozzi C (2012) Long-term results of sorafenib in advanced-stage hepatocellular carcinoma: what can we learn from routine clinical practice? Expert Rev Anticancer Ther 12(7):869–875. doi:10.1586/era.12.58

    Article  CAS  PubMed  Google Scholar 

  5. Tanaka TU, Desai A (2008) Kinetochore-microtubule interactions: the means to the end. Curr Opin Cell Biol 20(1):53–63. doi:10.1016/j.ceb.2007.11.005

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Ferretti C, Totta P, Fiore M, Mattiuzzo M, Schillaci T, Ricordy R, Di Leonardo A, Degrassi F (2010) Expression of the kinetochore protein Hec1 during the cell cycle in normal and cancer cells and its regulation by the pRb pathway. Cell Cycle 9(20):4174–4182

    Article  CAS  PubMed  Google Scholar 

  7. Chen Y, Riley DJ, Zheng L, Chen P-L, Lee W-H (2002) Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is essential for faithful chromosome segregation. J Biol Chem 277(51):49408–49416. doi:10.1074/jbc.M207069200

    Article  CAS  PubMed  Google Scholar 

  8. Wu G, Qiu XL, Zhou L, Zhu J, Chamberlin R, Lau J, Chen PL, Lee WH (2008) Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal. Cancer Res 68(20):8393–8399. doi:10.1158/0008-5472.CAN-08-1915

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Diaz-Rodriguez E, Sotillo R, Schvartzman JM, Benezra R (2008) Hec1 overexpression hyperactivates the mitotic checkpoint and induces tumor formation in vivo. Proc Natl Acad Sci USA 105(43):16719–16724. doi:10.1073/pnas.0803504105

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Qu Y, Li J, Cai Q, Liu B (2014) Hec1/Ndc80 is overexpressed in human gastric cancer and regulates cell growth. J Gastroenterol 49(3):408–418. doi:10.1007/s00535-013-0809-y

    Article  CAS  PubMed  Google Scholar 

  11. Puisieux A, Galvin K, Troalen F, Bressac B, Marcais C, Galun E, Ponchel F, Yakicier C, Ji J, Ozturk M (1993) Retinoblastoma and p53 tumor suppressor genes in human hepatoma cell lines. FASEB J Off Publ Fed Am Soc Exp Biol 7(14):1407–1413

    CAS  Google Scholar 

  12. Hu CM, Zhu J, Guo XE, Chen W, Qiu XL, Ngo B, Chien R, Wang YV, Tsai CY, Wu G, Kim Y, Lopez R, Chamberlin AR, Lee EH, Lee WH (2014) Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism. Oncogene. doi:10.1038/onc.2014.67

    Google Scholar 

  13. Huang LY, Lee YS, Huang JJ, Chang CC, Chang JM, Chuang SH, Kao KJ, Tsai YJ, Tsai PY, Liu CW, Lin HS, Lau JY (2014) Characterization of the biological activity of a potent small molecule Hec1 inhibitor TAI-1. J Exp clin Cancer Res CR 33:6. doi:10.1186/1756-9966-33-6

    Article  Google Scholar 

  14. Lee YS, Chuang SH, Huang LY, Lai CL, Lin YH, Yang JY, Liu CW, Yang SC, Lin HS, Chang CC, Lai JY, Jian PS, Lam K, Chang JM, Lau JY, Huang JJ (2014) Discovery of 4-Aryl-N-arylcarbonyl-2-aminothiazoles as Hec1/Nek2 Inhibitors. Part I: Optimization of in Vitro Potencies and Pharmacokinetic Properties. Journal of medicinal chemistry. doi:10.1021/jm401990s

  15. Huang LY, Chang CC, Lee YS, Chang JM, Huang JJ, Chuang SH, Kao KJ, Lau GM, Tsai PY, Liu CW, Lin HS, Lau JY (2014) Activity of a novel Hec1-targeted anticancer compound against breast cancer cell lines in vitro and in vivo. Mol Cancer Ther. doi:10.1158/1535-7163.MCT-13-0700

    Google Scholar 

  16. Wei R, Ngo B, Wu G, Lee WH (2011) Phosphorylation of the Ndc80 complex protein, HEC1, by Nek2 kinase modulates chromosome alignment and signaling of the spindle assembly checkpoint. Mol Biol Cell 22(19):3584–3594. doi:10.1091/mbc.E11-01-0012

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Zheng L, Chen Y, Lee WH (1999) Hec1p, an evolutionarily conserved coiled-coil protein, modulates chromosome segregation through interaction with SMC proteins. Mol Cell Biol 19(8):5417–5428

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Hasumura S, Sujino H, Nagamori S, Kameda H (1988) Establishment and characterization of a human hepatocellular carcinoma cell line JHH-4. Hum Cell 1(1):98–100

    CAS  PubMed  Google Scholar 

  19. Homma S, Nagamori S, Fujise K, Hasumura S, Sujino H, Matsuura T, Shimizu K, Niiya M, Kameda H (1990) Establishment and characterization of a human hepatocellular carcinoma cell line JHH-7 producing alpha -fetoprotein and carcinoembryonic antigen–changes in secretion of AFP and CEA from JHH-7 cells after heat treatment. Hum Cell 3(2):152–157

    CAS  PubMed  Google Scholar 

  20. Ku JL, Park JG (2005) Biology of SNU cell lines. Cancer Res Treat Off J Korean Cancer Assoc 37(1):1–19. doi:10.4143/crt.2005.37.1.1

    Google Scholar 

  21. Park JG, Lee JH, Kang MS, Park KJ, Jeon YM, Lee HJ, Kwon HS, Park HS, Yeo KS, Lee KU et al (1995) Characterization of cell lines established from human hepatocellular carcinoma. Int J cancer J Int du Cancer 62(3):276–282

    Article  CAS  Google Scholar 

  22. Chen Y, Riley DJ, Chen PL, Lee WH (1997) HEC, a novel nuclear protein rich in leucine heptad repeats specifically involved in mitosis. Mol Cell Biol 17(10):6049–6056

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Staib F, Hussain SP, Hofseth LJ, Wang XW, Harris CC (2003) TP53 and liver carcinogenesis. Hum Mutat 21(3):201–216. doi:10.1002/humu.10176

    Article  CAS  PubMed  Google Scholar 

  24. Charette N, De Saeger C, Horsmans Y, Leclercq I, Starkel P (2013) Salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis through DR5 and survivin-dependent mechanisms. Cell Death Dis 4:e471. doi:10.1038/cddis.2012.200

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Parekh P, Motiwale L, Naik N, Rao KV (2011) Downregulation of cyclin D1 is associated with decreased levels of p38 MAP kinases, Akt/PKB and Pak1 during chemopreventive effects of resveratrol in liver cancer cells. Exp Toxic Pathol Off J Gesellschaft fur Toxikologische Pathologie 63(1–2):167–173. doi:10.1016/j.etp.2009.11.005

    Article  CAS  Google Scholar 

  26. Li G, Zhang S, Fang H, Yan B, Zhao Y, Feng L, Ma X, Ye X (2013) Aspirin overcomes Navitoclax-resistance in hepatocellular carcinoma cells through suppression of Mcl-1. Biochem Biophysi Res Commun 434(4):809–814. doi:10.1016/j.bbrc.2013.04.018

    Article  CAS  Google Scholar 

  27. Sundin LJ, Guimaraes GJ, Deluca JG (2011) The NDC80 complex proteins Nuf2 and Hec1 make distinct contributions to kinetochore-microtubule attachment in mitosis. Mol Biol Cell 22(6):759–768. doi:10.1091/mbc.E10-08-0671

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Thomas MB, O’Beirne JP, Furuse J, Chan AT, Abou-Alfa G, Johnson P (2008) Systemic therapy for hepatocellular carcinoma: cytotoxic chemotherapy, targeted therapy and immunotherapy. Ann Surg Oncol 15(4):1008–1014. doi:10.1245/s10434-007-9705-0

    Article  PubMed  Google Scholar 

  29. Chu JS, Ge FJ, Zhang B, Wang Y, Silvestris N, Liu LJ, Zhao CH, Lin L, Brunetti AE, Fu YL, Wang J, Paradiso A, Xu JM (2013) Expression and prognostic value of VEGFR-2, PDGFR-beta, and c-Met in advanced hepatocellular carcinoma. J Exp Clin Cancer Res CR 32(1):16. doi:10.1186/1756-9966-32-16

    Article  CAS  Google Scholar 

  30. Seitz SJ, Schleithoff ES, Koch A, Schuster A, Teufel A, Staib F, Stremmel W, Melino G, Krammer PH, Schilling T, Muller M (2010) Chemotherapy-induced apoptosis in hepatocellular carcinoma involves the p53 family and is mediated via the extrinsic and the intrinsic pathway. Int J cancer J Int du Cancer 126(9):2049–2066. doi:10.1002/ijc.24861

    CAS  Google Scholar 

  31. Chun E, Lee KY (2004) Bcl-2 and Bcl-xL are important for the induction of paclitaxel resistance in human hepatocellular carcinoma cells. Biochem Biophysi Res Commun 315(3):771–779. doi:10.1016/j.bbrc.2004.01.118

    Article  CAS  Google Scholar 

  32. Takahashi M, Saito H, Atsukawa K, Ebinuma H, Okuyama T, Ishii H (2003) Bcl-2 prevents doxorubicin-induced apoptosis of human liver cancer cells. Hepatol Res Off J Japan Soc Hepatol 25(2):192–201

    Article  CAS  Google Scholar 

  33. Chen KF, Chen HL, Tai WT, Feng WC, Hsu CH, Chen PJ, Cheng AL (2011) Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther 337(1):155–161. doi:10.1124/jpet.110.175786

    Article  CAS  PubMed  Google Scholar 

  34. Siena S, Sartore-Bianchi A, Di Nicolantonio F, Balfour J, Bardelli A (2009) Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst 101(19):1308–1324. doi:10.1093/jnci/djp280

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We thank our team members at the Development Center for Biotechnology, Jeffrey Chia-Lin Wang, Drs. Chi-feng Chang, Jui-Lien Huang, Horace Loh, and Ms. Lihyan Lee, and Mr. Kuo-ming Yu for their unfailing support. This research was funded by Taivex Therapeutics and the Development Center for Biotechnology grant issued by the Ministry of Economic Affairs of the Republic of China (102-EC-17-A-01-05-0739, to Chia-ling Wang).

Conflict of interest

LYLH, CCC, KJK, GML, JYNL, and RGG are either employees or consultants of Taivex Therapeutics, which owns the rights of this compound. YSL, JJH, SHC, JMC, YJT, PYT, CWL, and HSL are employees of Development Center of Biotechnology, which collaborated with Taivex Therapeutics and will receive royalty of this compound if successfully approved and marketed.

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Authors and Affiliations

  1. Taivex Therapeutics Corporation, 17th Floor, No. 3, Yuanqu Street, Nangang District, Taipei City, 115, Taiwan, ROC

    Lynn YL Huang, Chia-chi Chang, Kuo-Jang Kao, Gillian MG Lau, Robert G. Gish & Johnson YN Lau

  2. Development Center for Biotechnology, 101, Lane 169, Kangning Street, Xizhi District, New Taipei City, 22180, Taiwan, ROC

    Ying-Shuan Lee, Jiann-Jyh Huang, Shih-Hsien Chuang, Jia-Ming Chang, Pei-Yi Tsai, Chia-wei Liu & Her-Sheng Lin

  3. University of California, San Diego, 9500 Gilman Dr., La Jolla, CA, 92093, USA

    Robert G. Gish

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  1. Lynn YL Huang
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Correspondence to Lynn YL Huang.

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Huang, L.Y., Chang, Cc., Lee, YS. et al. Inhibition of Hec1 as a novel approach for treatment of primary liver cancer. Cancer Chemother Pharmacol 74, 511–520 (2014). https://doi.org/10.1007/s00280-014-2540-7

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  • DOI: https://doi.org/10.1007/s00280-014-2540-7

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