Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Contribution of HSP90 Cleavage to the Cytotoxic Effect of Suberoylanilide Hydroxamic Acid In Vivo and the Involvement of TXNIP in HSP90 Cleavage

  • Sangkyu Park (Biotechnology Research Institute, Chungbuk National University) ;
  • Dongbum Kim (Institute of Medical Science, College of Medicine, Hallym University) ;
  • Haiyoung Jung (Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • In Pyo Choi (Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Hyung-Joo Kwon (Institute of Medical Science, College of Medicine, Hallym University) ;
  • Younghee Lee (Biotechnology Research Institute, Chungbuk National University)
  • Received : 2023.05.30
  • Accepted : 2023.07.21
  • Published : 2024.01.01
Download PDF
⟨ Previous Next ⟩

Abstract

Heat shock protein (HSP) 90 is expressed in most living organisms, and several client proteins of HSP90 are necessary for cancer cell survival and growth. Previously, we found that HSP90 was cleaved by histone deacetylase (HDAC) inhibitors and proteasome inhibitors, and the cleavage of HSP90 contributes to their cytotoxicity in K562 leukemia cells. In this study, we first established mouse xenograft models with K562 cells expressing the wild-type or cleavage-resistant mutant HSP90β and found that the suppression of tumor growth by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was interrupted by the mutation inhibiting the HSP90 cleavage in vivo. Next, we investigated the possible function of thioredoxin interacting protein (TXNIP) in the HSP90 cleavage induced by SAHA. TXNIP is a negative regulator for thioredoxin, an antioxidant protein. SAHA transcriptionally induced the expression of TXNIP in K562 cells. HSP90 cleavage was induced by SAHA also in the thymocytes of normal mice and suppressed by an anti-oxidant and pan-caspase inhibitor. When the thymocytes from the TXNIP knockout mice and their wild-type littermate control mice were treated with SAHA, the HSP90 cleavage was detected in the thymocytes of the littermate controls but suppressed in those of the TXNIP knockout mice suggesting the requirement of TXNIP for HSP90 cleavage. We additionally found that HSP90 cleavage was induced by actinomycin D, β-mercaptoethanol, and p38 MAPK inhibitor PD169316 suggesting its prevalence. Taken together, we suggest that HSP90 cleavage occurs also in vivo and contributes to the anti-cancer activity of various drugs in a TXNIP-dependent manner.

Keywords

Acknowledgement

This research was supported by grants from the National Research Foundation (2018R1A2B6002504, NRF2021R1A2C1006767) funded by the Ministry of Science and ICT in the Republic of Korea.

References

  1. Bali, P., Pranpat, M., Bradner, J., Balasis, M., Fiskus, W., Guo, F., Rocha, K., Kumaraswamy, S., Boyapalle, S., Atadja, P., Seto, E. and Bhalla, K. (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 280, 26729-26734. https://doi.org/10.1074/jbc.C500186200
  2. Beck, R., Dejeans, N., Glorieux, C., Creton, M., Delaive, E., Dieu, M., Raes, M., Leveque, P., Gallez, B., Depuydt, M., Collet, J. F., Calderon, P. B. and Verrax, J. (2012) Hsp90 is cleaved by reactive oxygen species at a highly conserved N-terminal amino acid motif. PLos One 7, e40795. https://doi.org/10.1371/journal.pone.0040795
  3. Beck, R., Verrax, J., Gonze, T., Zappone, M., Pedrosa, R. C., Taper, H., Feron, O. and Calderon, P. B. (2009) Hsp90 cleavage by an oxidative stress leads to its client proteins degradation and cancer cell death. Biochem. Pharmacol. 77, 375-383. https://doi.org/10.1016/j.bcp.2008.10.019
  4. Bolden, J. E., Peart, M. J. and Johnstone, R. W. (2006) Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5, 769-784. https://doi.org/10.1038/nrd2133
  5. Butler, L. M., Zhou, X., Xu, W. S., Scher, H. I., Rifkind, R. A., Marks, P. A. and Richon, V. M. (2002) The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc. Natl. Acad. Sci. U. S. A. 99, 11700-11705. https://doi.org/10.1073/pnas.182372299
  6. Castro, J. P., Fernando, R., Reeg, S., Meinl, W., Almeida, H. and Grune, T. (2019) Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation: a novel gain-of-function mechanism. Redox. Biol. 21, 101108. https://doi.org/10.1016/j.redox.2019.101108
  7. Chen, H., Xia, Y., Fang, D., Hawke, D. and Lu, Z. (2009) Caspase-10-mediated heat shock protein 90 beta cleavage promotes UVB irradiation-induced cell apoptosis. Mol. Cell. Biol. 29, 3657-3664. https://doi.org/10.1128/MCB.01640-08
  8. Chen, K. S. and DeLuca, H. F. (1994) Isolation and characterization of a novel cDNA from HL-60 cells treated with 1,25-dihydroxyvitamin D-3. Biochim. Biophys. Acta 1219, 26-32. https://doi.org/10.1016/0167-4781(94)90242-9
  9. Choi, J. K., Park, S., Park, J. A., Shin, H., Choi, Y. and Lee, Y. (2022) HDAC inhibitor and proteasome inhibitor induce cleavage and exosome-mediated secretion of HSP90 in mouse pluripotent stem cells. Biochem. Biophys. Res. Commun. 620, 29-34. https://doi.org/10.1016/j.bbrc.2022.06.057
  10. Chung, J. W., Jeon, J. H., Yoon, S. R. and Choi, I. (2006) Vitamin D-3 upregulated protein 1 (VDUP1) is a regulator for redox signaling and stress-mediated diseases. J. Dermatol. 33, 662-669. https://doi.org/10.1111/j.1346-8138.2006.00156.x
  11. Crawford, L. J., Walker, B. and Irvine, A. E. (2011) Proteasome inhibitors in cancer therapy. J. Cell Commun. Signal. 5, 101-110. https://doi.org/10.1007/s12079-011-0121-7
  12. Curran, M. P. and McKeage, K. (2009) Bortezomib: a review of its use in patients with multiple myeloma. Drugs 69, 859-888. https://doi.org/10.2165/00003495-200969070-00006
  13. Dickson, M. A., Okuno, S. H., Keohan, M. L., Maki, R. G., D'Adamo, D. R., Akhurst, T. J., Antonescu, C. R. and Schwartz, G. K. (2013) Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors. Ann. Oncol. 24, 252-257. https://doi.org/10.1093/annonc/mds275
  14. Dokmanovic, M., Clarke, C. and Marks, P. A. (2007) Histone deacetylase inhibitors: overview and perspectives. Mol. Cancer Res. 5, 981-989. https://doi.org/10.1158/1541-7786.MCR-07-0324
  15. Eckschlager, T., Plch, J., Stiborova, M. and Hrabeta, J. (2017) Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci. 18, 1414. https://doi.org/10.3390/ijms18071414
  16. Fritsch, J., Fickers, R., Klawitter, J., Sarchen, V., Zingler, P., Adam, D., Janssen, O., Krause, E. and Schutze, S. (2016) TNF induced cleavage of HSP90 by cathepsin D potentiates apoptotic cell death. Oncotarget 7, 75774-75789. https://doi.org/10.18632/oncotarget.12411
  17. Junn, E., Han, S. H., Im, J. Y., Yang, Y., Cho, E. W., Um, H. D., Kim, D. K., Lee, K. W., Han, P. L., Rhee, S. G. and Choi, I. (2000) Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J. Immunol. 164, 6287-6295. https://doi.org/10.4049/jimmunol.164.12.6287
  18. Kaimul, A. M., Nakamura, H., Masutani, H. and Yodoi, J. (2007) Thioredoxin and thioredoxin-binding protein-2 in cancer and metabolic syndrome. Free Radical. Biol. Med. 43, 861-868. https://doi.org/10.1016/j.freeradbiomed.2007.05.032
  19. Karkoulis, P. K., Stravopodis, D. J., Margaritis, L. H. and Voutsinas, G. E. (2010) 17-Allylamino-17-demethoxygeldanamycin induces downregulation of critical Hsp90 protein clients and results in cell cycle arrest and apoptosis of human urinary bladder cancer cells. BMC Cancer 10, 481. https://doi.org/10.1186/1471-2407-10-481
  20. Kleeff, J., Kornmann, M., Sawhney, H. and Korc, M. (2000) Actinomycin D induces apoptosis and inhibits growth of pancreatic cancer cells. Int. J. Cancer 86, 399-407. https://doi.org/10.1002/(SICI)1097-0215(20000501)86:3<399::AID-IJC15>3.0.CO;2-G
  21. Kwon, H. J., Won, Y. S., Suh, H. W., Jeon, J. H., Shao, Y., Yoon, S. R., Chung, J. W., Kim, T. D., Kim, H. M., Nam, K. H., Yoon, W. K., Kim, D. G., Kim, J. H., Kim, Y. S., Kim, D. Y., Kim, H. C. and Choi, I. (2010) Vitamin D3 upregulated protein 1 suppresses TNF-alpha-induced NF-kappaB activation in hepatocarcinogenesis. J. Immunol. 185, 3980-3989. https://doi.org/10.4049/jimmunol.1000990
  22. Langeveld, M., Gamadia, L. E. and ten Berge, I. J. M. (2006) T-lymphocyte subset distribution in human spleen. Eur. J. Clin. Invest. 36, 250-256. https://doi.org/10.1111/j.1365-2362.2006.01626.x
  23. Lee, K. N., Kang, H. S., Jeon, J. H., Kim, E. M., Yoon, S. R., Song, H., Lyu, C. Y., Piao, Z. H., Kim, S. U., Han, Y. H., Song, S. S., Lee, Y. H., Song, K. S., Kim, Y. M., Yu, D. Y. and Choi, I. (2005) VDUP1 is required for the development of natural killer cells. Immunity 22, 195-208. https://doi.org/10.1016/j.immuni.2004.12.012
  24. Liu, S. H., Lin, C. H., Liang, F. P., Chen, P. F., Kuo, C. D., Alam, M. M., Maiti, B., Hung, S. K., Chi, C. W., Sun, C. M. and Fu, S. L. (2014) Andrographolide downregulates the v-Src and Bcr-Abl oncoproteins and induces Hsp90 cleavage in the ROS-dependent suppression of cancer malignancy. Biochem. Pharmacol. 87, 229-242. https://doi.org/10.1016/j.bcp.2013.10.014
  25. Livak, K. J. and Schmittgen, T. D. (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25, 402-408. https://doi.org/10.1006/meth.2001.1262
  26. Lu, D. F., Wang, Y. S., Li, C., Wei, G. J., Chen, R., Dong, D. M. and Yao, M. (2015) Actinomycin D inhibits cell proliferations and promotes apoptosis in osteosarcoma cells. Int. J. Clin. Exp. Med. 8, 1904-1911.
  27. Modi, S., Stopeck, A., Linden, H., Solit, D., Chandarlapaty, S., Rosen, N., D'Andrea, G., Dickler, M., Moynahan, M. E., Sugarman, S., Ma, W. N., Patil, S., Norton, L., Hannah, A. L. and Hudis, C. (2011) HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin. Cancer Res. 17, 5132-5139. https://doi.org/10.1158/1078-0432.CCR-11-0072
  28. Modi, S., Stopeck, A. T., Gordon, M. S., Mendelson, D., Solit, D. B., Bagatell, R., Ma, W., Wheler, J., Rosen, N., Norton, L., Cropp, G. F., Johnson, R. G., Hannah, A. L. and Hudis, C. A. (2007) Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2-overexpressing breast cancer: a phase I dose-escalation study. J. Clin. Oncol. 25, 5410-5417. https://doi.org/10.1200/JCO.2007.11.7960
  29. Nishiyama, A., Matsui, M., Iwata, S., Hirota, K., Masutani, H., Nakamura, H., Takagi, Y., Sono, H., Gon, Y. and Yodoi, J. (1999) Identification of thioredoxin-binding protein-2/vitamin D-3 up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J. Biol. Chem. 274, 21645-21650. https://doi.org/10.1074/jbc.274.31.21645
  30. Park, S., Jeon, J. H., Park, J. A., Choi, J. K. and Lee, Y. (2021) Cleavage of HSP90beta induced by histone deacetylase inhibitor and proteasome inhibitor modulates cell growth and apoptosis. Cell Stress Chaperones 26, 129-139. https://doi.org/10.1007/s12192-020-01161-6
  31. Park, S., Park, J. A., Jeon, J. H. and Lee, Y. (2019) Traditional and novel mechanisms of heat shock protein 90 (HSP90) inhibition in cancer chemotherapy including HSP90 cleavage. Biomol. Ther. (Seoul) 27, 423-434. https://doi.org/10.4062/biomolther.2019.051
  32. Park, S., Park, J. A., Kim, Y. E., Song, S., Kwon, H. J. and Lee, Y. (2015) Suberoylanilide hydroxamic acid induces ROS-mediated cleavage of HSP90 in leukemia cells. Cell Stress Chaperones 20, 149-157. https://doi.org/10.1007/s12192-014-0533-4
  33. Park, S., Park, J. A., Yoo, H., Park, H. B. and Lee, Y. (2017) Proteasome inhibitor-induced cleavage of HSP90 is mediated by ROS generation and caspase 10-activation in human leukemic cells. Redox Biol. 13, 470-476. https://doi.org/10.1016/j.redox.2017.07.010
  34. Schroder, J., Schumacher, U. and Bockelmann, L. C. (2020) Thioredoxin interacting protein (TXNIP) is differentially expressed in human tumor samples but is absent in human tumor cell line xenografts: implications for its use as an immunosurveillance marker. Cancers (Basel) 12, 3028. https://doi.org/10.3390/cancers12103028
  35. Scollay, R. and Shortman, K. (1983) Thymocyte subpopulations - an experimental review, including flow cytometric cross-correlations between the major murine thymocyte markers. Thymus 5, 245-295.
  36. Scroggins, B. T., Robzyk, K., Wang, D., Marcu, M. G., Tsutsumi, S., Beebe, K., Cotter, R. J., Felts, S., Toft, D., Karnitz, L., Rosen, N. and Neckers, L. (2007) An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol. Cell 25, 151-159. https://doi.org/10.1016/j.molcel.2006.12.008
  37. Shen, S. C., Yang, L. Y., Lin, H. Y., Wu, C. Y., Su, T. H. and Chen, Y. C. (2008) Reactive oxygen species-dependent HSP90 protein cleavage participates in arsenical As(+3)- and MMA(+3)-induced apoptosis through inhibition of telomerase activity via JNK activation. Toxicol. Appl. Pharmacol. 229, 239-251. https://doi.org/10.1016/j.taap.2008.01.018
  38. Wang, M. J., Liu, S., Liu, Y. and Zheng, D. (2007) Actinomycin D enhances TRAIL-induced caspase-dependent and -independent apoptosis in SH-SY5Y neuroblastoma cells. Neurosci. Res. 59, 40-46. https://doi.org/10.1016/j.neures.2007.05.010
  39. Welch, W. J. (1993) How cells respond to stress. Sci. Am. 268, 56-64. https://doi.org/10.1038/scientificamerican0593-56
  40. Wu, Y., Wang, X., Chang, S., Lu, W., Liu, M. and Pang, X. (2016) beta-Lapachone induces NAD(P)H:quinone oxidoreductase-1- and oxidative stress-dependent heat shock protein 90 cleavage and inhibits tumor growth and angiogenesis. J. Pharmacol. Exp. Ther. 357, 466-475. https://doi.org/10.1124/jpet.116.232694
  41. Yoshioka, J., Schulze, P. C., Cupesi, M., Sylvan, J. D., MacGillivray, C., Gannon, J., Huang, H. and Lee, R. T. (2004) Thioredoxin-interacting protein controls cardiac hypertrophy through regulation of thioredoxin activity. Circulation 109, 2581-2586. https://doi.org/10.1161/01.CIR.0000129771.32215.44
  42. Zhou, J. B. and Chng, W. J. (2013) Roles of thioredoxin binding protein (TXNIP) in oxidative stress, apoptosis and cancer. Mitochondrion 13, 163-169. https://doi.org/10.1016/j.mito.2012.06.004