The Role of Two Isoforms of Heat Shock Protein Hsp90 in Resistance of Human Fibrosarcoma Cells HT1080 to Hsp90 Inhibitors and Cytoxic Drugs

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Abstract

Intracellular heat shock protein 90 (Hsp90) performs important functions related to the folding, stabilization and degradation of various proteins in the cell, and prevents protein aggregation and denaturation under various types of stress. There are two isoforms of Hsp90, the inducible isoform Hsp90α and the constitutive isoform Hsp90β. Hsp90β is thought to play a key role in the functioning of housekeeping proteins, while Hsp90α plays an important role in the cellular response to stress. We explored for the first time the role of two Hsp90 isoforms in ensuring the resistance of human fibrosarcoma cells HT1080 to Hsp90 inhibitors and a number of antitumor drugs with different mechanisms of action. Both Hsp90 isoforms have been shown to make a comparable contribution to cell resistance to Hsp90 inhibitors, and one Hsp90 isoform is not able to completely compensate for the absence of another Hsp90 isoform under the influence of Hsp90 inhibitors. Both Hsp90 isoforms are also involved in ensuring cell resistance to cytotoxic anticancer drugs, with Hsp90α likely playing a more important role than Hsp90β in protecting cells from the cytotoxic effects of sorafenib and nocodazole. In the case of cisplatin, each of the Hsp90 isoforms is able to largely compensate for the absence of the other isoform. In the case of doxorubicin, bortezomib, sorafenib, paclitaxel, and nocodazole, the absence of one of the Hsp90 isoforms led to a significant decrease in cell resistance to anticancer drugs, which was especially pronounced in the case of paclitaxel and nocodazole. The Hsp90 inhibitor 17-AAG potentiates the effect of cytotoxic drugs on cells, providing the most pronounced synergy with paclitaxel and nocodazole. As a result, the important role of both Hsp90 isoforms in cell resistance to Hsp90 inhibitors and anticancer drugs with different mechanisms of action was determined for the first time. The data obtained indicate the prospects of developing Hsp90αor Hsp90β-specific inhibitors for antitumor therapy and their combined use with known antitumor drugs.

About the authors

V. S Petrenko

Institute of Cell Biophysics, Russian Academy of Sciences

Email: 79182797935@yandex.ru
Pushchino, Russia

O. S Morenkov

Institute of Cell Biophysics, Russian Academy of Sciences

Pushchino, Russia

Yu. Yu Skarga

Institute of Cell Biophysics, Russian Academy of Sciences

Pushchino, Russia

M. A Zhmurina

Institute of Cell Biophysics, Russian Academy of Sciences

Pushchino, Russia

V. V Vrublevskaya

Institute of Cell Biophysics, Russian Academy of Sciences

Pushchino, Russia

References

  1. Biebl M. M. and Buchner J. Structure, function, and regulation of the Hsp90 machinery. Perspect. Biol., 11 (9), a034017 (2019). doi: 10.1101/cshperspect.a034017
  2. Neckers L., Mollapour M., and Tsutsumi S. The complex dance of the molecular chaperone Hsp90. Trends Biochem. Sci., 34, 223 (2009). doi: 10.1016/j.tibs.2009.01.006
  3. Maiti S. and Picard D. Cytosolic Hsp90 isoform-specific functions and clinical significance. Biomolecules, 12, 1166 (2022). doi: 10.3390/biom12091166
  4. Wandinger S. K., Richter K., and Buchner J. The Hsp90 chaperone machinery. J. Biol. Chem., 283, 18473 (2008). doi: 10.1038/nrm.2017.20
  5. Prodromou C. The ‘active life’ of Hsp90 complexes. Biochim. Biophys. Acta, 1823, 614 (2012). doi: 10.1016/j.bbamcr.2011.07.020
  6. Zuehlke A. D., Beebe R., Neckers L., and Prince T. Regulation and function of the human HSP90AA1 gene. Gene., 570, 8 (2015). doi: 10.1016/j.gene.2015.06.018
  7. Hoter A., El-Sabban M. E., and Naim H. Y. The HSP90 family: Structure, regulation, function, and implications in health and disease. Int. J. Mol. Sci., 19 (9), 2560 (2018). doi: 10.3390/ijms19092560
  8. Pick E., Kluger Y., Giltnane J. M., Moeder C., Camp R. L., Rimm D. L., and Kluger H. M. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res., 67, 2932 (2007).
  9. Ciocca D. R., Arrigo A. P., and Calderwood S. K. Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: An update. Arch. Toxicol., 87, 19 (2013). doi: 10.1007/s00204-012-0918-z
  10. Dernovsek J. and Tomasic T. Following the design path of isoform-selective Hsp90 inhibitors: Small differences, great opportunities. Pharmacol. Ther., 245, 108396 (2023). doi: 10.1016/j.pharmthera.2023.108396
  11. Sanchez J., Carter T. R., Cohen M. S., and Blagg B. S. Old and new approaches to target the Hsp90 chaperone. Curr. Cancer Drug Targets., 20 (4), 253 (2020). doi: 10.2174/1568009619666191202101330
  12. Miyata Y., Nakamoto H., and Neckers L. The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm. Des., 19 (3), 347 (2013). DOI: 10.2174/ 138161213804143725
  13. Neckers L., Blagg B., Haystead T., Trepel J. B., Whitesell L., and Picard D. Methods to validate Hsp90 inhibitor specificity, to identify off-target effects, and to rethink approaches for further clinical development. Cell Stress & Chaperones., 23 (4), 467 (2018). doi: 10.1007/s12192-018-0877-2
  14. Park S., Park J. A., Jeon J. Y., and Lee Y. Traditional and novel mechanisms of heat shock protein 90 (HSP90) Inhibition in cancer chemotherapy including HSP90 cleavage. Biomol. Ther., 27 (5), 423 (2019). doi: 10.4062/biomolther.2019.051
  15. Gorska M. and Popowska U. Geldanamycin and its derivatives as Hsp90 inhibitors. Front. Biosci. (Landmark Ed)., 17 (6), 2269 (2012). doi: 10.2741/4050
  16. Saad Z. U., Robert B., and Zihai L. 17 AAG for HSP90 inhibition in cancer — from bench to bedside. Curr Mol. Med., 9 (5), 654 (2009). doi: 10.2174/156652409788488757
  17. Taiyab A., Srinivas U. K., and Sreedhar A. S. 17-(Allylamino)-17-demethoxygeldanamycin combination with diferuloylmethane selectively targets mitogen kinase pathway in a human neuroblastoma cell line. J. Cancer Ther., 1, 197 (2010). doi: 10.4236/jct.2010.14031
  18. Biamonte M. A., Water R. V., Arndt J. W., Scannevin R. H., Perret D., and Lee W. Heat shock protein 90: Inhibitors in clinical trials. J. Med. Chem., 53 (1), 3 (2010). doi: 10.1021/jm9004708
  19. Hong D., Said R., Falchook G., Naing A., Moulder S., Tsimberidou A., Galluppi G., Dakappagari N., Storgard C., Kurzrock R., and Rosen L.S. Phase I study of BIIB028, a selective heat shock protein 90 inhibitor, in patients with refractory metastatic or locally advanced solid tumors. Clin. Cancer Res., 19 (17), 4824 (2013). doi: 10.1158/1078-0432.CCR-13-0477
  20. Soti C., Racz A., and Csermely P. A nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. N-terminal nucleotide binding unmasks a C-terminal binding pocket. J. Biol. Chem., 277 (9), 7066 (2002). doi: 10.1074/jbc.M105568200
  21. Berko Y. A., FunmilolaA. F., andAkala E. O. Fabrication of paclitaxel and 17AAG-loaded poly-E-caprolactone nanoparticles for breast cancer treatment. J. Pharm. Drug Deliv. Res., 10 (1), 196 (2021). doi: 10.48047/ecb/2023.12.si4.1190
  22. Katragadda U., Fan W., Wang Y., Wang Y., Teng Q., and Tan C. Combined delivery of paclitaxel and tanespimycin via micellar nanocarriers: pharmacokinetics, efficacy and metabolomic analysis. PLoS One., 8 (3), e58619 (2013). doi: 10.1371/journal.pone.0058619
  23. Ui T., Morishima K., Saito S., Sakuma Y., Fujii H., Hosoya Y., Ishikawa S., Aburatani H., Fukayama M., Niki T., and Yasuda Y. The HSP90 inhibitor 17-N-allylamino-17 -demethoxy geldanamycin ( 17-AAG) synergizes with cisplatin and induces apoptosis in cisplatin-resistant esophageal squamous cell carcinoma cell lines via the Akt/XIAP pathway. Oncol Rep., 31 (2), 619 (2014). doi: 10.3892/or.2013.2899
  24. Schmidt L., Issa I. I., Haraldsdóttir H., Hald J. J., Schmitz A., Due H., and Dybkær K. Hsp90 inhibition sensitizes DLBCL cells to cisplatin. Cancer Chemother. Pharmacol., 89, 431 (2022). doi: 10.1007/s00280-022-04407-5
  25. Li Z. N. and Luo Y. HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review). Oncol Rep., 49 (1), 6 (2023). doi: 10.3892/or.2022.8443
  26. Magyar C. T. J., Vashist Y. K., Stroka D., Kim-Fuchs C., Berger M. D., and Banz V. Heat shock protein 90 (HSP90) inhibitors in gastrointestinal cancer: where do we currently stand? — A systematic review. J. Cancer Res. Clin. Oncol., 149, 8039 (2023). doi: 10.1007/s00432-023-04689-z
  27. Lang J. E., Forero-Torres A., Yee D., Yau C., Wolf D., Park J., Parker B. A., Chien A. J., Wallace A. M., Murthy R., Albain K. S., and Ellis E. D. Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer. NPJ Breast Cancer, 8 (1), 128 (2022). doi: 10.1038/s41523-022-00493-z
  28. Becker B., Multhof, G., Farkas B., Wild P. J., Landthaler M., and Stolz W. Induction ofHsp90 protein expression in malignant melanomas and melanoma metastases . Exp. Dermatol., 13 (1), 27 (2004). doi: 10.1111/j.0906-6705.2004.00114.x
  29. Petrenko V., Vrublevskaya V, Bystrova M., Masulis I., Kopylova E., Skarga Y., Zhmurina M., Morenkov O.Proliferation, migration, and resistance to oxidative and thermal stresses of HT1080 cells with knocked out genes encoding Hsp90a and Hsp90ß Biochem. Biophys. Res. Commun. , 674, 62 (2023). doi: 10.1016/j.bbrc.2023.06.076
  30. Chiang T. W., Le Sage C., Larrieu D., Demir M., and Jackson S. P. CRISPR-Cas9(D10A) nickase-based genotypic and phenotypic screening to enhance genome editing. Sci. Rep., 6, 24356 (2016). doi: 10.1038/srep24356
  31. Dasari S. and Tchounwou P. B. Cisplatin in cancer therapy: molecular mechanisms of action. Eur. J. Pharmacol., 740, 364 (2014). doi: 10.1016/j.ejphar.2014.07.025
  32. Kciuk M., GielecinskaA., Mujwar S., Kołat D., Kałuzińska-Kołat Z., Celik E., and Kontek R. Doxorubicin — an agent with multiple mechanisms of anticancer activity. Cells, 12 (4), 659 (2023). doi: 10.3390/cells12040659
  33. Bonvini P., Zorzi E., Basso G., and Rosolen A. Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma. Leukemia, 21 (4), 838 (2007). doi: 10.1038/sj.leu.2404528
  34. Wilhelm S. M., Adnane L., and Newell P. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther., 7 (10), 3129 (2008). doi: 10.1158/1535-7163.MCT-08-0013
  35. Wang T. H., Wang H. S., and Soong Y. K. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer, 88 (11), 2619 (2000). doi: 10.1002/1097-0142(20000601)88:11<2619::aid-cn-cr26>3.0.co;2-j
  36. Kallas A., Pook M, Maimets M., Zimmermann K., and Maimets T. Nocodazole treatment decreases expression of pluripotency markers nanog and Oct4 in human embryonic stem cells. PLoS One., 6 (4), e19114 (2011). doi: 10.1371/journal.pone.0019114
  37. Mo Q., Zhang Y., Jin X., Gao Y., Wu Y., Hao X., Gao Q., and Chen P. Geldanamycin, an inhibitor of Hsp90, increases paclitaxel-mediated toxicity in ovarian cancer cells through sustained activation of the p38/H2AX axis. Tumour Biol., 37 (11), 14745 (2016). doi: 10.1007/s13277-016-5297-2

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