Effect of the HSF1 inhibitor Cl-43 on tumors and non-transformed cells

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Аннотация

The occurrence of severe side effects in patients undergoing chemotherapy remains a significant clinical challenge. Therefore, the urgent task is to search for tumor-specific therapies that target opposing responses in non-transformed and tumorigenic cells. HSF1 is known to be an important marker of cancer progression and its transcriptional activity products allow tumor cells to escape the adverse effects of anticancer therapies. Thus, drugs inhibiting HSF1 activity hold promise as a therapeutic strategy. Our study shows that using the cardenolide group’s HSF1 activity inhibitor, CL-43, provides cytoprotective effects on primary, untransformed dermal fibroblast (DF-2) cells, making them less sensitive to etoposide, whereas we observed an increase in sensitivity in the DLD1 tumor cell line. Furthermore, our results show that CL-43 interferes with the intranuclear transport of the active form of HSF1, increasing its activity and consequently the synthesis of HSP70 in human fibroblasts, while suppressing this activity in tumor cells in a dose-dependent manner. Our findings demonstrate the unique potential of CL-43 as a tumor-specific compound with high therapeutic value.

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Авторлар туралы

S. Vladimirova

Institute of Cytology, Russian Academy of Sciences

Email: nikotina.ad@gmail.com
Ресей, St. Petersburg, 194064

B. Margulis

Institute of Cytology, Russian Academy of Sciences

Email: nikotina.ad@gmail.com
Ресей, St. Petersburg, 194064

I. Guzhova

Institute of Cytology, Russian Academy of Sciences

Email: nikotina.ad@gmail.com
Ресей, St. Petersburg, 194064

A. Nikotina

Institute of Cytology, Russian Academy of Sciences

Хат алмасуға жауапты Автор.
Email: nikotina.ad@gmail.com
Ресей, St. Petersburg, 194064

Әдебиет тізімі

  1. Ajmeera D., Ajumeera R. 2023. Drug repurposing: A novel strategy to target cancer stem cells and therapeutic resistance. Genes Dis. V. 11. P. 148. https://doi.org/10.1016/j.gendis.2022.12.013
  2. Banerjee M., Cui X., Li Z., Yu H., Cai L., Jia X., Daheng H., Wang C., Gao T., Xie Z. 2018. Na/K-ATPase Y260 phosphorylation-mediated Src regulation in control of aerobic glycolysis and tumor growth. Sci. Rep. V. 8. P. 1. http://dx.doi.org/10.1038/s41598-018-29995-2
  3. Botelho A.F.M., Pierezan F., Soto-Blanco B., Melo M.M. 2019. A review of cardiac glycosides: structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential. Toxicon. V. 158. P. 63. https://doi.org/10.1016/j.toxicon.2018.11.429
  4. Carpenter R.L., Paw I., Dewhirst M.W. and Lo H-W. 2015. 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. V. 34. P. 546.
  5. Carpenter R.L., Yesim G-P. 2019. HSF1 as a cancer biomarker and therapeutic target. Curr. Cancer Drug Targets. V. 19. P. 515.
  6. Cerella C., Dicato M., Diederich M. 2013. Assembling the puzzle of anti-cancer mechanisms triggered by cardiac glycosides. Mitochondrion. V. 13. P. 225. http://dx.doi.org/10.1016/j.mito.2012.06.003
  7. Dai C., Sampson S.B. 2016. HSF1: guardian of proteostasis in cancer Chengkai. Trends Cell Biol. V. 26. P. 17.
  8. Dai C. 2018. The heat-shock, or HSF1-mediated proteotoxic stress, response in cancer: from proteomic stability to oncogenesis. Philos. Trans. R. Soc. B. Biol. Sci. V. 373. P. 20160525.
  9. Gao Q.X., Zhou G.X., Lin S.J., Paus R., Yue Z.C. 2019. How chemotherapy and radiotherapy damage the tissue: comparative biology lessons from feather and hair models. Exper. Dermatol. V. 28. P. 413.
  10. Guo Y., Guettouche T., Fenna M., Boellmann F., Pratt W.B., Toft D.O., Smith D.F., Voellmy R. 2001. Evidence for a mechanism of repression of Heat Shock Factor 1 transcriptional activity by a multichaperone complex. J. Biol. Chem. V. 276. P. 45791. http://dx.doi.org/10.1074/jbc.M105931200
  11. Irby R.B., Yeatman T.J. 2000. Role of Src expression and activation in human cancer. Oncogene. V. 19. P. 5636. http://dx.doi.org/10.1038/sj.onc.1203912
  12. Kim N., Yim H.Y., He N., Lee C.J., Kim J.H., Choi J.S., Lee H.S., Kim S., Jeong E., Song M., Jeon S-M., Kim W-Y., Mills G.B., Cho Y-Y., Yoon S. 2016. Cardiac glycosides display selective efficacy for STK11 mutant lung cancer. Sci. Rep. V. 6. P. 29721.
  13. Neef D.W., Jaeger A., Gomez-Pastor R., Willmund F., Frydman J., Thiele D.J. 2014. A direct regulatory interaction between chaperonin TRiC and stress responsive transcription factor HSF1. Cell Rep. V. 9. P. 955.
  14. Neudegger T., Verghese J., Hayer-Hartl M., Hartl F.U., Bracher A. 2016. Structure of human heat-shock transcription factor 1 in complex with DNA. Nat. Struct. Mol. Biol. V. 23. P. 140.
  15. Nikotina A.D., Koludarova L., Komarova E.Y., Mikhaylova E.R., Aksenov N.D., Suezov R., Kartzev V.G., Margulis B.A., Guzhova I.V. 2018. Discovery and optimization of cardenolides inhibiting HSF1 activation in human colon HCT-116 cancer cells. Oncotarget. V. 9. P. 27268.
  16. Shen J., Zhan Y., Li H., Wang Z. 2020. Ouabain impairs cancer metabolism and activates AMPK-Src signaling pathway in human cancer cell lines. Acta Pharmacol. Sin. V. 41. P. 110. http://dx.doi.org/10.1038/s41401-019-0290-0
  17. Wang Y., Zhan Y., Xu R., Shao R., Jiang J., Wang Z. 2015. Src mediates extracellular signal-regulated kinase 1/2 activation and autophagic cell death induced by cardiac glycosides in human non-small cell lung cancer cell lines. Mol. Carcinog. V. 54. P. 26.

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2. Fig. 1. Changes in the cellular index of DLD1 and DF-2 cells in the presence of etoposide and/or CL-43. Cells were seeded into 16-well E-plates and cultured in the presence of 10 μM etoposide and/or 0.25 μM CL-43 for 20 h; The recording was carried out with registration of the cell index every 10 minutes.

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3. Fig. 2. Change in the amount of pHSF1 and its target HSP70 in DLD1 (a) and DF-2 (b) cells under the influence of CL-43. On the left - immunoblots of cell lysates after their cultivation for 20 hours in the presence of 0.125, 0.25 and 0.5 µM CL-43. On the right is a graphical representation of changes in the intensity of bands on blots; the intensity of each zone was normalized to tubulin, which was used as a load control. The intensity of the zones was assessed using the ImageLab program.

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4. Fig. 3. Localization of active HSF1(pHSF1) in DLD1 cells (a) and its quantitative distribution (b) after treatment with CL-43 at a concentration of 250 nM; a – confocal microscopy; After fixation, the cells were reacted with primary antibodies to pHSF1 and secondary antibodies conjugated with the Alexa 488 tag. Nuclei were additionally stained with DAPI (blue). Cells in which DMSO was added at a concentration corresponding to the variant with the addition of a CL-43 solution served as a control; scale bar: 5 µm; b – histograms show the average values and standard deviations (of 100 cells) of fluorescence intensity (arbitrary units) of pHSF1 in the cytoplasm and nucleus; (***) – the difference is significant at p < 0.005.

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5. Fig. 4. Localization of active HSF1 (pHSF1) and its quantitative distribution (b) in DF-2 cells (a) after treatment with CL-43 at a concentration of 250 nM. The explanations are the same as for Fig. 3. (*) – the difference is significant at p < 0.05; # – no significant differences.

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