Skip to main content
SpringerLink
Log in

NG25, a novel inhibitor of TAK1, suppresses KRAS-mutant colorectal cancer growth in vitro and in vivo

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

KRAS mutations are one of the most prevalent genetic alterations in colorectal cancer (CRC). Although directly targeting KRAS still is a challenge in anti-cancer therapies, alternatively inhibiting KRAS related signaling pathways has been approached effectively. Here we firstly reported that MAP kinase, transforming growth factor-β-activated kinase 1 (TAK1), commonly expressed in CRC cell lines and significantly associated with KRAS mutation status. Inhibition of TAK1 by the small molecular inhibitor NG25 could inhibit CRC cells proliferation in vitro and in vivo, especially in KRAS-mutant cells. NG25 induced caspase-dependent apoptosis in KRAS-mutant cells and in orthotopic CRC mouse models by regulating the B-cell lymphoma-2 (Bcl-2) family and the inhibitor of apoptosis protein (IAP) family. Besides inhibiting molecules downstream of MAPK, including ERK, JNK and p38 phosphorylation, NG25 could block NF-κB activation in KRAS-mutant cells. As a target gene of NF-κB, down-regulated XIAP expression may be not only involved in apoptosis induced by NG25, but also reducing the formation of TAK1-XIAP complex that can activate TAK1 downstream signaling pathways, which forms a positive feedback loop to further induce apoptosis in KRAS-mutant CRC cells. Together, these findings indicated that TAK1 is an important kinase for survival of CRCs harboring KRAS mutations, and that NG25 may be a potential therapeutic strategy for KRAS-mutant CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. https://doi.org/10.1002/ijc.29210

    Article  CAS  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A (2017) Cancer Statistics, 2017. CA Cancer J Clin 67(1):7–30. https://doi.org/10.3322/caac.21387

    Article  Google Scholar 

  3. De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar S (2011) KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 12(6):594–603. https://doi.org/10.1016/s1470-2045(10)70209-6

    Article  PubMed  Google Scholar 

  4. Herreros-Villanueva M, Chen CC, Yuan SS, Liu TC, Er TK (2014) KRAS mutations: analytical considerations. Clin Chim Acta 431:211–220. https://doi.org/10.1016/j.cca.2014.01.049

    Article  CAS  PubMed  Google Scholar 

  5. Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ, Bishop WR, Pai JK (1997) K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 272(22):14459–14464

    Article  CAS  PubMed  Google Scholar 

  6. Singh A, Sweeney MF, Yu M, Burger A, Greninger P, Benes C, Haber DA, Settleman J (2012) TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell 148(4):639–650. https://doi.org/10.1016/j.cell.2011.12.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K (1995) Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270(5244):2008–2011

    Article  CAS  PubMed  Google Scholar 

  8. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K (1999) The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398(6724):252–256. https://doi.org/10.1038/18465

    Article  CAS  PubMed  Google Scholar 

  9. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412(6844):346–351. https://doi.org/10.1038/35085597

    Article  CAS  PubMed  Google Scholar 

  10. Chen YR, Tan TH (2000) The c-Jun N-terminal kinase pathway and apoptotic signaling (review). Int J Oncol 16(4):651–662

    CAS  PubMed  Google Scholar 

  11. Mihaly SR, Ninomiya-Tsuji J, Morioka S (2014) TAK1 control of cell death. Cell Death Differ 21(11):1667–1676. https://doi.org/10.1038/cdd.2014.123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tan L, Nomanbhoy T, Gurbani D, Patricelli M, Hunter J, Geng J, Herhaus L, Zhang J, Pauls E, Ham Y, Choi HG, Xie T, Deng X, Buhrlage SJ, Sim T, Cohen P, Sapkota G, Westover KD, Gray NS (2015) Discovery of type II inhibitors of TGFbeta-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2). J Med Chem 58(1):183–196. https://doi.org/10.1021/jm500480k

    Article  CAS  PubMed  Google Scholar 

  13. Wang Z, Zhang H, Shi M, Yu Y, Wang H, Cao WM, Zhao Y, Zhang H (2016) TAK1 inhibitor NG25 enhances doxorubicin-mediated apoptosis in breast cancer cells. Sci Rep 6:32737. https://doi.org/10.1038/srep32737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hrabe JE, O’Leary BR, Fath MA, Rodman SN, Button AM, Domann FE, Spitz DR, Mezhir JJ (2015) Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor beta-activated kinase 1 (TAK1) inhibition in KRAS-mutated colon cancer cells. Redox Biol 5:319–327. https://doi.org/10.1016/j.redox.2015.06.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Khanbolooki S, Nawrocki ST, Arumugam T, Andtbacka R, Pino MS, Kurzrock R, Logsdon CD, Abbruzzese JL, McConkey DJ (2006) Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Mol Cancer Ther 5(9):2251–2260. https://doi.org/10.1158/1535-7163.mct-06-0075

    Article  CAS  PubMed  Google Scholar 

  16. Du J, Wang Y, Chen D, Ji G, Ma Q, Liao S, Zheng Y, Zhang J, Hou Y (2016) BAY61-3606 potentiates the anti-tumor effects of TRAIL against colon cancer through up-regulating DR4 and down-regulating NF-kappaB. Cancer Lett 383(2):145–153. https://doi.org/10.1016/j.canlet.2016.10.002

    Article  CAS  PubMed  Google Scholar 

  17. Yun SI, Kim HH, Yoon JH, Park WS, Hahn MJ, Kim HC, Chung CH, Kim KK (2015) Ubiquitin specific protease 4 positively regulates the WNT/beta-catenin signaling in colorectal cancer. Mol Oncol 9(9):1834–1851. https://doi.org/10.1016/j.molonc.2015.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. He X, Shi W, Wen S, SUN Y, Ling G, Shen k, Peng C, Chen B, Wang J (2015) The establishment and evaluation of orthotopic colorectal cancer model in cecum mesentery triangle Chinese J Oncol 37(6):418–421. https://doi.org/10.3760/cma.j.issn.0253-3766.2015.06.004

    Article  Google Scholar 

  19. Rumble JM, Duckett CS (2008) Diverse functions within the IAP family. J Cell Sci 121(Pt 21):3505–3507. https://doi.org/10.1242/jcs.040303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chua CWL, Chong DQ, Kanesvaran R, Tai WMD, Tham CK, Tan P, Earnest A, Tan IB (2014) The prognostic impact of KRAS mutation in colorectal cancer patients: a meta-analysis of phase III clinical trials. J Clin Oncol 32(15_suppl):e14515–e14515. https://doi.org/10.1200/jco.2014.32.15_suppl.e14515

    Article  Google Scholar 

  21. Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, Richman S, Chambers P, Seymour M, Kerr D, Gray R, Quirke P (2011) Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 29(10):1261–1270. https://doi.org/10.1200/JCO.2010.30.1366

    Article  PubMed  Google Scholar 

  22. Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA (2011) Systematic review: Anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med 154(1):37–49. https://doi.org/10.7326/0003-4819-154-1-201101040-00006

    Article  PubMed  Google Scholar 

  23. Gavrilescu LC, Molnar A, Murray L, Garafalo S, Kehrl JH, Simon AR, Van Etten RA, Kyriakis JM (2012) Retraction for Zhong et al. GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38. Proc Natl Acad Sci USA 109(13):5134. https://doi.org/10.1073/pnas.1203089109

    Article  CAS  PubMed  Google Scholar 

  24. Wang H, Chen Z, Li Y, Ji Q (2017) NG25, an inhibitor of transforming growth factorbetaactivated kinase 1, ameliorates neuronal apoptosis in neonatal hypoxicischemic rats. Mol Med Rep. https://doi.org/10.3892/mmr.2017.8024

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lewis J, Burstein E, Reffey SB, Bratton SB, Roberts AB, Duckett CS (2004) Uncoupling of the signaling and caspase-inhibitory properties of X-linked inhibitor of apoptosis. J Biol Chem 279(10):9023–9029. https://doi.org/10.1074/jbc.M312891200

    Article  CAS  PubMed  Google Scholar 

  26. Vaux DL, Silke J (2005) IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 6(4):287–297. https://doi.org/10.1038/nrm1621

    Article  CAS  PubMed  Google Scholar 

  27. Mahoney DJ, Cheung HH, Mrad RL, Plenchette S, Simard C, Enwere E, Arora V, Mak TW, Lacasse EC, Waring J, Korneluk RG (2008) Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci USA 105(33):11778–11783. https://doi.org/10.1073/pnas.0711122105

    Article  PubMed  Google Scholar 

  28. Varfolomeev E, Goncharov T, Fedorova AV, Dynek JN, Zobel K, Deshayes K, Fairbrother WJ, Vucic D (2008) c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. J Biol Chem 283(36):24295–24299. https://doi.org/10.1074/jbc.C800128200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zarnegar BJ, Wang Y, Mahoney DJ, Dempsey PW, Cheung HH, He J, Shiba T, Yang X, Yeh WC, Mak TW, Korneluk RG, Cheng G (2008) Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol 9(12):1371–1378. https://doi.org/10.1038/ni.1676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Miss. Yue Zhang (Brown University) for language editing. This work was supported by research grants from the National Natural Science Foundation of China (Nos. 81471551 and 81630054).

Author information

Author notes

  1. Qizhao Ma and Ling Gu have contributed equally to this work.

Authors and Affiliations

  1. West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Qizhao Ma, Shiping Liao, Yanjiang Zheng, Shu Zhang, Yueyan Cao, Ji Zhang & Yufang Wang

  2. Laboratory of Hematology/Oncology, Department of Pediatric Hematology/Oncology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Ling Gu

Authors
  1. Qizhao Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ling Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shiping Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanjiang Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yueyan Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ji Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yufang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ji Zhang or Yufang Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All animal experiments are in accordance with International Guidelines and Protocols and approved by the Institutional Animal Care and Use Committee at the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2756 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, Q., Gu, L., Liao, S. et al. NG25, a novel inhibitor of TAK1, suppresses KRAS-mutant colorectal cancer growth in vitro and in vivo. Apoptosis 24, 83–94 (2019). https://doi.org/10.1007/s10495-018-1498-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-018-1498-z

Keywords

Search

Navigation