Skip to main content
SpringerLink
Log in

CL-43, a New Inhibitor of HSF1 Activity, Inhibits Epithelial-Mesenchymal Transition of DLD1 Colon Cancer Cells

  • Published:
Cell and Tissue Biology Aims and scope Submit manuscript

Abstract

Colorectal cancer is highly metastatic. In a quarter of patients with tumors of this type, liver metastases are detected already at the time of diagnosis. Therefore, the search for drugs that can reduce the metastatic activity of cells is an important task. A tumor experiences constant stress, resulting in an increased activity of the transcription factor HSF1, which is able to trigger the synthesis of heat shock proteins. This increases the resistance of cancer cells to both stress and antitumor therapy. It has been shown recently that HSF1 plays a critical role in the process of the epithelial–mesenchymal transition (EMT) underling the formation of metastases. Here, we show that a new inhibitor of HSF1 activity, CL-43, is capable of suppressing EMT that is induced by TGFβ1. CL-43 significantly reduced the migration and proliferative potency of DLD1 cells treated with TGFβ1. Analysis of vimentin level showed that cell treatment with CL-43 cells reduced this EMT marker and returned the expression and localization of E-cadherin in the cells to the original pattern. These findings suggest that CL-43 has therapeutic potential for treatment of colorectal tumors.

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.

Similar content being viewed by others

REFERENCES

  1. Bessen, H.A., Therapeutic and toxic effects of Digitalis: William Withering, 1785, J. Emerg. Med., 1986, vol. 4, pp. 243–248.

    Article  CAS  Google Scholar 

  2. Bradford, M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding, Anal. Biochem., 1976, vol. 72, pp. 248–254.

    Article  CAS  Google Scholar 

  3. Carpenter, R.L., Paw, I., Dewhirst, M.W., and Lo, H.W., Akt phosphorylates and activates HSF-1 independent of heat shock, leading to slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells, Oncogene, 2015, vol. 34, pp. 546–557.

    Article  CAS  Google Scholar 

  4. Chen, K., Qian, W., Li, J., Jiang, Z., Cheng, L., Yan, B., Cao, J., Sun, L., Zhou, C., Lei, M., Duan, W., Ma, J., Ma, Q., and Ma, Z., Loss of AMPK activation promotes the invasion and metastasis of pancreatic cancer through an HSF1-dependent pathway, Mol. Oncol., 2017, vol. 11, pp. 1475–1492.

    Article  CAS  Google Scholar 

  5. Jacobs, A.T. and Marnett, L.J., HSF1-mediated BAG3 expression attenuates apoptosis in 4-hydroxynonenal-treated colon cancer cells via stabilization of anti-apoptotic Bcl-2 proteins, J. Biol. Chem., 2009, vol. 284, pp. 9176–9183.

    Article  CAS  Google Scholar 

  6. Juhasz, K., Lipp, A.M., Nimmervoll, B., Sonnleitner, A., Hesse, J., Haselgruebler, T., and Balogi, Z., The complex function of Hsp70 in metastatic cancer, Cancers (Basel), 2013, vol. 6, pp. 42–66.

    Article  Google Scholar 

  7. Kim, S.J., Lee, S.C., Kang, H.G., Gim, J., Lee, K.H., Lee, S.H., and Chun, K.H., Heat shock factor 1 predicts poor prognosis of gastric cancer, Yonsei Med. J., 2018, vol. 59, pp. 1041–1048.

    Article  CAS  Google Scholar 

  8. Liao, T.T. and Yang, M.H., Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness, Mol. Oncol., 2017, vol. 11, pp. 792–804.

    Article  Google Scholar 

  9. Nikotina, A.D., Koludarova, L., Komarova, E.Y., Mikhaylova, E.R., Aksenov, N.D., Suezov, R., Kartzev, V.G., Margulis, B.A., and Guzhova, I.V., Discovery and optimization of cardenolides inhibiting HSF1 activation in human colon HCT-116 cancer cells, Oncotarget, 2018, vol. 9, pp. 27 268–27 279.

    Article  Google Scholar 

  10. Paul, S., Ghosh, S, .Mandal, S., Sau, S., and Pal, M., NRF2 transcriptionally activates the heat shock factor 1 promoter under oxidative stress and affects survival and migration potential of MCF7 cells, J. Biol. Chem., 2018, vol. 293, pp. 19303–19316.

    Article  CAS  Google Scholar 

  11. Qin, G., Luo, M., Chen, J., Dang, Y., Chen, G., Li, L., Zeng, J., Lu, Y., and Yang, J., Reciprocal activation between MMP-8 and TGF-β1 stimulates EMT and malignant progression of hepatocellular carcinoma, Cancer Lett., 2016, vol. 374, pp. 85–95.

    Article  CAS  Google Scholar 

  12. Riihimäki, M., Hemminki, A., Sundquist, J., and Hemminki, K., Patterns of metastasis in colon and rectal cancer, Sci. Rep., 2016, vol. 6, p. 29765. https://doi.org/10.1038/srep29765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Roche, J., The epithelial-to-mesenchymal transition in cancer, Cancers (Basel), 2018, vol. 10, no. 2. pii: E52. https://doi.org/10.3390/cancers10020052

    Article  CAS  PubMed  Google Scholar 

  14. Slingerland, M., Cerella, C., Guchelaar, H.J., Diederich, M., and Gelderblom, H., Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials, Invest. New Drugs, 2013, vol. 31, pp. 1087–1094.

    Article  CAS  Google Scholar 

  15. Tang, Y., Herr, G., Johnson, W., Resnik, E., and Aho, J., Induction and analysis of epithelial to mesenchymal transition, J. Vis. Exp., 2013, vol. 78. https://doi.org/10.3791/50478

  16. Van der Geest, L.G., Lam-Boer, J., Koopman, M., Verhoef, C., Elferink, M.A., and de Wilt, J.H., Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases, Clin. Exp. Metastasis, 2015, vol. 32, pp. 457–465.

    Article  CAS  Google Scholar 

  17. Vega, S., Morales, A.V., Ocaña, O.H., Valdés, F., Fabregat, I., and Nieto, M.A., Snail blocks the cell cycle and confers resistance to cell death, Genes Dev., 2004, vol. 18, pp. 1131–1143.

    Article  CAS  Google Scholar 

  18. Vilaboa, N., Boré, A., Martin-Saavedra, F., Bayford, M., Winfield, N., Firth-Clark, S., Kirton, S.B., and Voellmy, R., New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumor cell survival, Nucleic Acids Res., 2017, vol. 45, pp. 5797–5817.

    Article  CAS  Google Scholar 

  19. Wendt, M.K., Tian, M., and Schiemann, W.P., Deconstructing the mechanisms and consequences of TGF-β-induced EMT during cancer progression, Cell Tiss. Res., 2012, vol. 347, pp. 85–101.

    Article  CAS  Google Scholar 

  20. Westerheide, S.D., Kawahara, T.L., Orton, K., and Morimoto, R.I., Triptolide, an inhibitor of the human heat shock response that enhances stress-induced cell death, J. Biol. Chem., 2006, vol. 281, pp. 9616–9622.

    Article  CAS  Google Scholar 

  21. Wrighton, K.H., Lin, X., and Feng, X.H., Critical regulation of TGFbeta signaling by Hsp90, Proc. Natl. Acad. Sci. U. S. A., 2008, vol. 105, pp. 9244–9249.

    Article  CAS  Google Scholar 

  22. Xi, C., Peng, S., Wu, Z., Zhou, Q., and Zhou, J., Toxicity of triptolide and the molecular mechanisms involved, Biomed. Pharmacother., 2017, vol. 90, pp. 531–541.

    Article  CAS  Google Scholar 

  23. Yang, W., Feng, B., Meng, Y., Wang, J., Geng, B., Cui, Q., Zhang, H., Yang, Y., and Yang, J., FAM3C–YY1 axis is essential for TGFβ-promoted proliferation and migration of human breast cancer MDA-MB-231 cells via the activation of HSF1, J. Cell Mol. Med., 2019. https://doi.org/10.1111/jcmm.14243

  24. Yokota, S., Kitahara, M., and Nagata, K., Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells, Cancer Res., 2000, vol. 60, pp. 2942–2948.

    CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

We thank N. Tararova (DAPCEL Inc., United States) for providing TGFβ1 and E.V. Martova for help in setting up experiments.

Funding

This work was supported by the Russian Science Foundation (project no. 19-74-20161) and Russian Foundation for Basic Research (project no. 18-34-00973).

Author information

Authors and Affiliations

  1. Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia

    A. D. Nikotina, B. A. Margulis & I. V. Guzhova

  2. InterBioScreen Ltd., 142432, Chernogolovka, Russia

    V. G. Kartsev

Authors
  1. A. D. Nikotina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. G. Kartsev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. A. Margulis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I. V. Guzhova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. V. Guzhova.

Ethics declarations

The authors declare that they have no conflict of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.

Additional information

Translated by I. Fridlyanskaya

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nikotina, A.D., Kartsev, V.G., Margulis, B.A. et al. CL-43, a New Inhibitor of HSF1 Activity, Inhibits Epithelial-Mesenchymal Transition of DLD1 Colon Cancer Cells. Cell Tiss. Biol. 13, 418–422 (2019). https://doi.org/10.1134/S1990519X19060075

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990519X19060075

Keywords:

Search

Navigation