Perspective | Published:

OPINION

Adapting to stress — chaperome networks in cancer

Nature Reviews Cancer (2018) | Download Citation

Abstract

In this Opinion article, we aim to address how cells adapt to stress and the repercussions chronic stress has on cellular function. We consider acute and chronic stress-induced changes at the cellular level, with a focus on a regulator of cellular stress, the chaperome, which is a protein assembly that encompasses molecular chaperones, co-chaperones and other co-factors. We discuss how the chaperome takes on distinct functions under conditions of stress that are executed in ways that differ from the one-on-one cyclic, dynamic functions exhibited by distinct molecular chaperones. We argue that through the formation of multimeric stable chaperome complexes, a state of chaperome hyperconnectivity, or networking, is gained. The role of these chaperome networks is to act as multimolecular scaffolds, a particularly important function in cancer, where they increase the efficacy and functional diversity of several cellular processes. We predict that these concepts will change how we develop and implement drugs targeting the chaperome to treat cancer.

  • Subscribe to Nature Reviews Cancer for full access:

    $265

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).

  2. 2.

    Lindquist, S. Protein folding sculpting evolutionary change. Cold Spring Harb. Symp. Quant. Biol. 74, 103–108 (2009).

  3. 3.

    Hartl, F. U., Bracher, A. & Hayer-Hartl, M. Molecular chaperones in protein folding and proteostasis. Nature 475, 324–332 (2011).

  4. 4.

    Laskey, R. A., Honda, B. M., Mills, A. D. & Finch, J. T. Nucleosomes are assembled by an acidic protein which binds histones and transfers them to DNA. Nature 275, 416–420 (1978).

  5. 5.

    Barraclough, R. & Ellis, R. J. Protein synthesis in chloroplasts. IX. Assembly of newly-synthesized large subunits into ribulose bisphosphate carboxylase in isolated intact pea chloroplasts. Biochim. Biophys. Acta 608, 19–31 (1980).

  6. 6.

    Goloubinoff, P., Gatenby, A. A. & Lorimer, G. H. GroE heat-shock proteins promote assembly of foreign prokaryotic ribulose bisphosphate carboxylase oligomers in Escherichia coli. Nature 337, 44–47 (1989).

  7. 7.

    Labbadia, J. & Morimoto, R. I. The biology of proteostasis in aging and disease. Annu. Rev. Biochem. 84, 435–464 (2015).

  8. 8.

    Horwich, A. L. Molecular chaperones in cellular protein folding: the birth of a field. Cell 157, 285–288 (2014).

  9. 9.

    Miller, S. B., Mogk, A. & Bukau, B. Spatially organized aggregation of misfolded proteins as cellular stress defense strategy. J. Mol. Biol. 427, 1564–1574 (2015).

  10. 10.

    Sontag, E. M., Samant, R. S. & Frydman, J. Mechanisms and functions of spatial protein quality control. Annu. Rev. Biochem. 86, 97–122 (2017).

  11. 11.

    Ritossa, F. New puffing pattern induced by temperature shock and Dnp in Drosophila. Experientia 18, 571–573 (1962).

  12. 12.

    Ritossa, F. M. Experimental activation of specific loci in polytene chromosomes of Drosophila. Exp. Cell Res. 35, 601–607 (1964).

  13. 13.

    Richter, K., Haslbeck, M. & Buchner, J. The heat shock response: life on the verge of death. Mol. Cell 40, 253–266 (2010).

  14. 14.

    Finka, A. & Goloubinoff, P. Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis. Cell Stress Chaperones 18, 591–605 (2013).

  15. 15.

    Finka, A., Mattoo, R. U. & Goloubinoff, P. Meta-analysis of heat- and chemically upregulated chaperone genes in plant and human cells. Cell Stress Chaperones 16, 15–31 (2011).

  16. 16.

    Wang, X. et al. Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 127, 803–815 (2006).

  17. 17.

    Taldone, T., Ochiana, S. O., Patel, P. D. & Chiosis, G. Selective targeting of the stress chaperome as a therapeutic strategy. Trends Pharmacol. Sci. 35, 48–59 (2014).

  18. 18.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

  19. 19.

    Brehme, M. et al. A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. Cell Rep. 9, 1135–1150 (2014).

  20. 20.

    Allan, R. K. & Ratajczak, T. Versatile TPR domains accommodate different modes of target protein recognition and function. Cell Stress Chaperones 16, 353–367 (2011).

  21. 21.

    Hadizadeh Esfahani, A., Sverchkova, A., Saez-Rodriguez, J., Schuppert, A. A. & Brehme, M. A systematic atlas of chaperome deregulation topologies across the human cancer landscape. PLoS Comput. Biol. 14, e1005890 (2018).

  22. 22.

    Ellis, R. J. Molecular chaperones: assisting assembly in addition to folding. Trends Biochem. Sci. 31, 395–401 (2006).

  23. 23.

    Ellis, R. J. Assembly chaperones: a perspective. Phil. Trans. R. Soc. B Biol. Sci. 368, 20110398 (2013).

  24. 24.

    Burgess, R. J. & Zhang, Z. Histone chaperones in nucleosome assembly and human disease. Nat. Struct. Mol. Biol. 20, 14–22 (2013).

  25. 25.

    Makhnevych, T. & Houry, W. A. The role of Hsp90 in protein complex assembly. Biochim. Biophys. Acta 1823, 674–682 (2012).

  26. 26.

    Palotai, R., Szalay, M. S. & Csermely, P. Chaperones as integrators of cellular networks: changes of cellular integrity in stress and diseases. IUBMB Life 60, 10–18 (2008).

  27. 27.

    Echtenkamp, F. J. et al. Global functional map of the p23 molecular chaperone reveals an extensive cellular network. Mol. Cell 43, 229–241 (2011).

  28. 28.

    Gong, Y. et al. An atlas of chaperone-protein interactions in Saccharomyces cerevisiae: implications to protein folding pathways in the cell. Mol. Syst. Biol. 5, 275 (2009).

  29. 29.

    McClellan, A. J. et al. Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell 131, 121–135 (2007).

  30. 30.

    Jamuczak, A. E., Eyers, C. E., Schwartz, J. M., Grant, C. M. & Hubbard, S. J. Quantitative proteomics and network analysis of SSA1 and SSB1 deletion mutants reveals robustness of chaperone HSP70 network in Saccharomyces cerevisiae. Proteomics 15, 3126–3139 (2015).

  31. 31.

    Gyurko, D. M., Soti, C., Stetak, A. & Csermely, P. System level mechanisms of adaptation, learning, memory formation and evolvability: the role of chaperone and other networks. Curr. Protein Pept. Sci. 15, 171–188 (2014).

  32. 32.

    Echeverria, P. C., Bernthaler, A., Dupuis, P., Mayer, B. & Picard, D. An interaction network predicted from public data as a discovery tool: application to the Hsp90 molecular chaperone machine. PLoS ONE 6, e26044 (2011).

  33. 33.

    Taipale, M. et al. A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 158, 434–448 (2014).

  34. 34.

    Harper, J. W. & Bennett, E. J. Proteome complexity and the forces that drive proteome imbalance. Nature 537, 328–338 (2016).

  35. 35.

    Rodina, A. et al. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 538, 397–401 (2016).

  36. 36.

    Barna, M. et al. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 456, 971–U979 (2008).

  37. 37.

    Elkon, R. et al. Myc coordinates transcription and translation to enhance transformation and suppress invasiveness. EMBO Rep. 16, 1723–1736 (2015).

  38. 38.

    Farkas, Z. et al. Hsp70-associated chaperones have a critical role in buffering protein production costs. eLife 7, e29845 (2018).

  39. 39.

    Trepel, J., Mollapour, M., Giaccone, G. & Neckers, L. Targeting the dynamic HSP90 complex in cancer. Nat. Rev. Cancer 10, 537–549 (2010).

  40. 40.

    Barrott, J. J. & Haystead, T. A. Hsp90, an unlikely ally in the war on cancer. FEBS J. 280, 1381–1396 (2013).

  41. 41.

    Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761–772 (2005).

  42. 42.

    Ambati, S. R. et al. Pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor, alone and in combination with bortezomib in Ewing sarcoma. Mol. Oncol. 8, 323–336 (2014).

  43. 43.

    Moulick, K. et al. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat. Chem. Biol. 7, 818–826 (2011).

  44. 44.

    Dunn, D. M. et al. c-Abl mediated tyrosine phosphorylation of Aha1 activates its co-chaperone function in cancer cells. Cell Rep. 12, 1006–1018 (2015).

  45. 45.

    Zuehlke, A. & Johnson, J. L. Hsp90 and co-chaperones twist the functions of diverse client proteins. Biopolymers 93, 211–217 (2010).

  46. 46.

    Wong, D. S. & Jay, D. G. Emerging roles of extracellular Hsp90 in cancer. Adv. Cancer Res. 129, 141–163 (2016).

  47. 47.

    Bachman, A. B. et al. Phosphorylation induced cochaperone unfolding promotes kinase recruitment and client class-specific Hsp90 phosphorylation. Nat. Commun. 9, 265 (2018).

  48. 48.

    Dahmer, M. K., Housley, P. R. & Pratt, W. B. Effects of molybdate and endogenous inhibitors on steroid-receptor inactivation, transformation, and translocation. Annu. Rev. Physiol. 46, 67–81 (1984).

  49. 49.

    Csermely, P. et al. ATP induces a conformational change of the 90-kDa heat shock protein (hsp90). J. Biol. Chem. 268, 1901–1907 (1993).

  50. 50.

    Hutchison, K. A., Stancato, L. F., Jove, R. & Pratt, W. B. The protein-protein complex between pp60v-src and hsp90 is stabilized by molybdate, vanadate, tungstate, and an endogenous cytosolic metal. J. Biol. Chem. 267, 13952–13957 (1992).

  51. 51.

    Kamal, A. et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407–410 (2003).

  52. 52.

    Shachrai, I., Zaslaver, A., Alon, U. & Dekel, E. Cost of unneeded proteins in E. coli is reduced after several generations in exponential growth. Mol. Cell 38, 758–767 (2010).

  53. 53.

    Matthews, J. M. Protein Dimerization and Oligomerization in Biology Vol. 747 (Springer Science+Business Media, 2012).

  54. 54.

    Matthews, J. M. & Sunde, M. Dimers, oligomers, everywhere. Adv. Exp. Med. Biol. 747, 1–18 (2012).

  55. 55.

    Tai, W., Guzman, M. L. & Chiosis, G. The epichaperome: the power of many as the power of one. Oncoscience 3, 266–267 (2016).

  56. 56.

    Wallace, E. W. et al. Reversible, specific, active aggregates of endogenous proteins assemble upon heat stress. Cell 162, 1286–1298 (2015).

  57. 57.

    Mackenzie, R. J. et al. Absolute protein quantification of the yeast chaperome under conditions of heat shock. Proteomics 16, 2128–2140 (2016).

  58. 58.

    Chadli, A., Ladjimi, M. M., Baulieu, E. E. & Catelli, M. G. Heat-induced oligomerization of the molecular chaperone Hsp90. Inhibition by ATP and geldanamycin and activation by transition metal oxyanions. J. Biol. Chem. 274, 4133–4139 (1999).

  59. 59.

    Lepvrier, E. et al. Hsp90 oligomerization process: how can p23 drive the chaperone machineries? Biochim. Biophys. Acta 1854, 1412–1424 (2015).

  60. 60.

    Ehrnsperger, M., Graber, S., Gaestel, M. & Buchner, J. Binding of non-native protein to Hsp25 during heat shock creates a reservoir of folding intermediates for reactivation. EMBO J. 16, 221–229 (1997).

  61. 61.

    Benaroudj, N., Batelier, G., Triniolles, F. & Ladjimi, M. M. Self-association of the molecular chaperone Hsc70. Biochemistry 34, 15282–15290 (1995).

  62. 62.

    Shirasu, K. & Schulze-Lefert, P. Complex formation, promiscuity and multi-functionality: protein interactions in disease-resistance pathways. Trends Plant Sci. 8, 252–258 (2003).

  63. 63.

    Good, M. C., Zalatan, J. G. & Lim, W. A. Scaffold proteins: hubs for controlling the flow of cellular information. Science 332, 680–686 (2011).

  64. 64.

    Cooper, M. G. The Cell: A Molecular Approach (Sinauer Associates, 2000).

  65. 65.

    Hartson, S. D. & Matts, R. L. Approaches for defining the Hsp90-dependent proteome. Biochim. Biophys. Acta 1823, 656–667 (2012).

  66. 66.

    Weidenauer, L., Wang, T., Joshi, S., Chiosis, G. & Quadroni, M. Proteomic interrogation of HSP90 and the insights for medical research. Expert Rev. Proteomics 14, 1105–1117 (2017).

  67. 67.

    Goldstein, R. L. et al. Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma. J. Clin. Invest. 125, 4559–4571 (2015).

  68. 68.

    Guo, A. et al. HSP90 stabilizes B cell receptor kinases in a multi-client interactome: PU-H71 induces CLL apoptosis in a cytoprotective microenvironment. Oncogene 36, 3441–3449 (2017).

  69. 69.

    Kucine, N. et al. Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias. Blood 126, 2479–2483 (2015).

  70. 70.

    Koppikar, P. et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature 489, 155–U222 (2012).

  71. 71.

    Marubayashi, S. et al. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J. Clin. Invest. 120, 3578–3593 (2010).

  72. 72.

    Tsai, C. L. et al. Stress-induced phosphoprotein-1 maintains the stability of JAK2 in cancer cells. Oncotarget 7, 50548–50563 (2016).

  73. 73.

    Zong, H. et al. A hyperactive signalosome in acute myeloid leukemia drives addiction to a tumor-specific Hsp90 species. Cell Rep. 13, 2159–2173 (2015).

  74. 74.

    Nayar, U. et al. Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies. Blood 122, 2837–2847 (2013).

  75. 75.

    Ojala, P. M. Naughty chaperone as a target for viral cancer. Blood 122, 2767–2768 (2013).

  76. 76.

    Baquero-Perez, B. & Whitehouse, A. Hsp70 isoforms are essential for the formation of Kaposi’s sarcoma-associated herpesvirus replication and transcription compartments. PLoS Pathog. 11, e1005274 (2015).

  77. 77.

    Anderson, I. et al. Heat shock protein 90 controls HIV-1 reactivation from latency. Proc. Natl Acad. Sci. USA 111, E1528–E1537 (2014).

  78. 78.

    Culjkovic-Kraljacic, B. et al. Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B cell lymphomas. Blood 127, 858–868 (2016).

  79. 79.

    Cerchietti, L. C. et al. A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Nat. Med. 15, 1369–1376 (2009).

  80. 80.

    Schwartz, H. et al. Combined HSP90 and kinase inhibitor therapy: insights from The Cancer Genome Atlas. Cell Stress Chaperones 20, 729–741 (2015).

  81. 81.

    Jarosz, D. F., Taipale, M. & Lindquist, S. Protein homeostasis and the phenotypic manifestation of genetic diversity: principles and mechanisms. Annu. Rev. Genet. 44, 189–216 (2010).

  82. 82.

    Bernards, R. A. Missing link in genotype-directed cancer therapy. Cell 151, 465–468 (2012).

  83. 83.

    Lu, X., Xiao, L., Wang, L. & Ruden, D. M. Hsp90 inhibitors and drug resistance in cancer: the potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs. Biochem. Pharmacol. 83, 995–1004 (2012).

  84. 84.

    Whitesell, L. & Lin, N. U. HSP90 as a platform for the assembly of more effective cancer chemotherapy. Biochim. Biophys. Acta 1823, 756–766 (2012).

  85. 85.

    Meyer, S. C. Mechanisms of resistance to JAK2 inhibitors in myeloproliferative neoplasms. Hematol. Oncol. Clin. North Am. 31, 627–642 (2017).

  86. 86.

    Neckers, L. & Workman, P. Hsp90 molecular chaperone inhibitors: are we there yet? Clin. Cancer Res. 18, 64–76 (2012).

  87. 87.

    Lackner, D. H., Schmidt, M. W., Wu, S., Wolf, D. A. & Bahler, J. Regulation of transcriptome, translation, and proteome in response to environmental stress in fission yeast. Genome Biol. 13, R25 (2012).

  88. 88.

    Hammond, C. M., Stromme, C. B., Huang, H., Patel, D. J. & Groth, A. Histone chaperone networks shaping chromatin function. Nat. Rev. Mol. Cell Biol. 18, 141–158 (2017).

  89. 89.

    Khurana, N. & Bhattacharyya, S. Hsp90, the concertmaster: tuning transcription. Front. Oncol. 5, 100 (2015).

  90. 90.

    Isaacs, J. S. Hsp90 as a “chaperone” of the epigenome: insights and opportunities for cancer therapy. Adv. Cancer Res. 129, 107–140 (2016).

  91. 91.

    Echtenkamp, F. J. et al. Hsp90 and p23 molecular chaperones control chromatin architecture by maintaining the functional pool of the RSC chromatin remodeler. Mol. Cell 64, 888–899 (2016).

  92. 92.

    Manjarrez, J. R., Sun, L., Prince, T. & Matts, R. L. Hsp90-dependent assembly of the DBC2/RhoBTB2-Cullin3 E3-ligase complex. PLoS ONE 9, e90054 (2014).

  93. 93.

    Patra, B. et al. A genome wide dosage suppressor network reveals genomic robustness. Nucleic Acids Res. 45, 255–270 (2017).

  94. 94.

    Albert, R., Jeong, H. & Barabasi, A. L. Error and attack tolerance of complex networks. Nature 406, 378–382 (2000).

  95. 95.

    Kitano, H. Biological robustness. Nat. Rev. Genet. 5, 826–837 (2004).

  96. 96.

    Felix, M. A. & Barkoulas, M. Pervasive robustness in biological systems. Nat. Rev. Genet. 16, 483–496 (2015).

  97. 97.

    Bandyopadhyay, S. et al. Rewiring of genetic networks in response to DNA damage. Science 330, 1385–1389 (2010).

  98. 98.

    Navlakha, S., He, X., Faloutsos, C. & Bar-Joseph, Z. Topological properties of robust biological and computational networks. J. R. Soc. Interface 11, 20140283 (2014).

  99. 99.

    Murphy, M. E. The HSP70 family and cancer. Carcinogenesis 34, 1181–1188 (2013).

  100. 100.

    Sherman, M. Y. & Gabai, V. L. Hsp70 in cancer: back to the future. Oncogene 34, 4153–4161 (2015).

  101. 101.

    Brodsky, J. L. & Chiosis, G. Hsp70 molecular chaperones: emerging roles in human disease and identification of small molecule modulators. Curr. Top. Med. Chem. 6, 1215–1225 (2006).

  102. 102.

    Assimon, V. A., Gillies, A. T., Rauch, J. N. & Gestwicki, J. E. Hsp70 protein complexes as drug targets. Curr. Pharm. Des. 19, 404–417 (2013).

  103. 103.

    Rerole, A. L., Jego, G. & Garrido, C. Hsp70: anti-apoptotic and tumorigenic protein. Methods Mol. Biol. 787, 205–230 (2011).

  104. 104.

    Lambert, J. P. et al. Mapping differential interactomes by affinity purification coupled with data-independent mass spectrometry acquisition. Nat. Methods 10, 1239–1245 (2013).

  105. 105.

    Jinwal, U. K. et al. Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J. 27, 1450–1459 (2013).

  106. 106.

    Gano, J. J. & Simon, J. A. A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1 as a novel ADP-dependent HSP90-interacting protein. Mol. Cell. Proteomics 9, 255–270 (2010).

  107. 107.

    Smith, J. R. et al. Restricting direct interaction of CDC37 with HSP90 does not compromise chaperoning of client proteins. Oncogene 34, 15–26 (2015).

  108. 108.

    Butler, L. M., Ferraldeschi, R., Armstrong, H. K., Centenera, M. M. & Workman, P. Maximizing the therapeutic potential of HSP90 inhibitors. Mol. Cancer Res. 13, 1445–1451 (2015).

  109. 109.

    Garcia-Carbonero, R., Carnero, A. & Paz-Ares, L. Inhibition of HSP90 molecular chaperones: moving into the clinic. Lancet Oncol. 14, e358–e369 (2013).

  110. 110.

    Alarcon, S. V. et al. Tumor-intrinsic and tumor-extrinsic factors impacting hsp90- targeted therapy. Curr. Mol. Med. 12, 1125–1141 (2012).

  111. 111.

    Jhaveri, K., Taldone, T., Modi, S. & Chiosis, G. Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim. Biophys. Acta 1823, 742–755 (2012).

  112. 112.

    Lehner, B. Molecular mechanisms of epistasis within and between genes. Trends Genet. 27, 323–331 (2011).

  113. 113.

    Collins, S. R., Weissman, J. S. & Krogan, N. J. From information to knowledge: new technologies for defining gene function. Nat. Methods 6, 721–723 (2009).

  114. 114.

    Ashworth, A., Lord, C. J. & Reis-Filho, J. S. Genetic interactions in cancer progression and treatment. Cell 145, 30–38 (2011).

  115. 115.

    Kim, G. et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin. Cancer Res. 21, 4257–4261 (2015).

  116. 116.

    Redig, A. J. & Janne, P. A. Basket trials and the evolution of clinical trial design in an era of genomic medicine. J. Clin. Oncol. 33, 975–977 (2015).

  117. 117.

    Smith, D. L. et al. The HSP90 inhibitor ganetespib potentiates the antitumor activity of EGFR tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancer. Target. Oncol. 10, 235–245 (2015).

  118. 118.

    Caldas-Lopes, E. et al. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc. Natl Acad. Sci. USA 106, 8368–8373 (2009).

  119. 119.

    Menezes, D. L. et al. The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo. Mol. Cancer Ther. 11, 730–739 (2012).

  120. 120.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01393509 (2018).

  121. 121.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01269593 (2018).

  122. 122.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03166085 (2017).

  123. 123.

    Lee, M. J. et al. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 149, 780–794 (2012).

  124. 124.

    Kanamaru, C. et al. Retinal toxicity induced by small-molecule Hsp90 inhibitors in beagle dogs. J. Toxicol. Sci. 39, 59–69 (2014).

  125. 125.

    Zhou, D. et al. A rat retinal damage model predicts for potential clinical visual disturbances induced by Hsp90 inhibitors. Toxicol. Appl. Pharmacol. 273, 401–409 (2013).

  126. 126.

    Shrestha, L. & Young, J. C. Function and chemotypes of human Hsp70 chaperones. Curr. Top. Med. Chem. 16, 2812–2828 (2016).

  127. 127.

    Li, X., Shao, H., Taylor, I. R. & Gestwicki, J. E. Targeting allosteric control mechanisms in heat shock protein 70 (Hsp70). Curr. Top. Med. Chem. 16, 2729–2740 (2016).

  128. 128.

    Goloudina, A. R., Demidov, O. N. & Garrido, C. Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett. 325, 117–124 (2012).

  129. 129.

    Stiegler, S. C. et al. A chemical compound inhibiting the Aha1-Hsp90 chaperone complex. J. Biol. Chem. 292, 17073–17083 (2017).

  130. 130.

    Jhaveri, K. et al. Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions. Expert Opin. Investig. Drugs 23, 611–628 (2014).

  131. 131.

    Prince, T. L. et al. Client proteins and small molecule inhibitors display distinct binding preferences for constitutive and stress-induced HSP90 isoforms and their conformationally restricted mutants. PLoS ONE 10, e0141786 (2015).

  132. 132.

    Woodford, M. R. et al. Impact of posttranslational modifications on the anticancer activity of Hsp90 inhibitors. Adv. Cancer Res. 129, 31–50 (2016).

  133. 133.

    Mollapour, M. & Neckers, L. Post-translational modifications of Hsp90 and their contributions to chaperone regulation. Biochim. Biophys. Acta 1823, 648–655 (2012).

  134. 134.

    Taldone, T. et al. Experimental and structural testing module to analyze paralogue-specificity and affinity in the Hsp90 inhibitors series. J. Med. Chem. 56, 6803–6818 (2013).

  135. 135.

    Sattin, S. et al. Activation of Hsp90 enzymatic activity and conformational dynamics through rationally designed allosteric ligands. Chemistry 21, 13598–13608 (2015).

  136. 136.

    Schopf, F. H., Biebl, M. M. & Buchner, J. The HSP90 chaperone machinery. Nat. Rev. Mol. Cell Biol. 18, 345–360 (2017).

  137. 137.

    Krukenberg, K. A., Street, T. O., Lavery, L. A. & Agard, D. A. Conformational dynamics of the molecular chaperone Hsp90. Q. Rev. Biophys. 44, 229–255 (2011).

  138. 138.

    Gooljarsingh, L. T. et al. A biochemical rationale for the anticancer effects of Hsp90 inhibitors: slow, tight binding inhibition by geldanamycin and its analogues. Proc. Natl Acad. Sci. USA 103, 7625–7630 (2006).

  139. 139.

    Beebe, K. et al. Posttranslational modification and conformational state of heat shock protein 90 differentially affect binding of chemically diverse small molecule inhibitors. Oncotarget 4, 1065–1074 (2013).

  140. 140.

    Tsaytler, P. A., Krijgsveld, J., Goerdayal, S. S., Rudiger, S. & Egmond, M. R. Novel Hsp90 partners discovered using complementary proteomic approaches. Cell Stress Chaperones 14, 629–638 (2009).

  141. 141.

    Matts, R. L. et al. A systematic protocol for the characterization of Hsp90 modulators. Bioorg. Med. Chem. 19, 684–692 (2011).

  142. 142.

    Copeland, R. A. The drug-target residence time model: a 10-year retrospective. Nat. Rev. Drug Discov. 15, 87–95 (2016).

  143. 143.

    de Witte, W. E., Danhof, M., van der Graaf, P. H. & de Lange, E. C. In vivo target residence time and kinetic selectivity: the association rate constant as determinant. Trends Pharmacol. Sci. 37, 831–842 (2016).

  144. 144.

    Patel, H. J., Modi, S., Chiosis, G. & Taldone, T. Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment. Expert Opin. Drug Dis. 6, 559–587 (2011).

  145. 145.

    Shrestha, L., Bolaender, A., Patel, H. J. & Taldone, T. Heat shock protein (HSP) drug discovery and development: targeting heat shock proteins in disease. Curr. Top. Med. Chem. 16, 2753–2764 (2016).

  146. 146.

    Ebong, I. O. et al. Heterogeneity and dynamics in the assembly of the heat shock protein 90 chaperone complexes. Proc. Natl Acad. Sci. USA 108, 17939–17944 (2011).

  147. 147.

    Zuehlke, A. D. et al. An Hsp90 co-chaperone protein in yeast is functionally replaced by site-specific posttranslational modification in humans. Nat. Commun. 8, 15328 (2017).

  148. 148.

    Voos, W. Chaperone-protease networks in mitochondrial protein homeostasis. Biochim. Biophys. Acta 1833, 388–399 (2013).

  149. 149.

    Sabnis, A. J. et al. Combined chemical-genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma. Proc. Natl Acad. Sci. USA 113, 9015–9020 (2016).

  150. 150.

    Altieri, D. C. Mitochondrial HSP90s and tumor cell metabolism. Autophagy 9, 244–245 (2013).

  151. 151.

    Patel, P. D. et al. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat. Chem. Biol. 9, 677–684 (2013).

  152. 152.

    Lee, A. S. Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat. Rev. Cancer 14, 263–276 (2014).

  153. 153.

    Carvalho, A. S., Rodriguez, M. S. & Matthiesen, R. Review and literature mining on proteostasis factors and cancer. Methods Mol. Biol. 1449, 71–84 (2016).

  154. 154.

    Brandvold, K. R. & Morimoto, R. I. The chemical biology of molecular chaperones — implications for modulation of proteostasis. J. Mol. Biol. 427, 2931–2947 (2015).

  155. 155.

    Gandolfi, S. et al. The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev. 36, 561–584 (2017).

  156. 156.

    Li, Z., Hartl, F. U. & Bracher, A. Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle. Nat. Struct. Mol. Biol. 20, 929–935 (2013).

  157. 157.

    Pratt, W. B. & Toft, D. O. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18, 306–360 (1997).

  158. 158.

    Davies, A. E. & Kaplan, K. B. Hsp90-Sgt1 and Skp1 target human Mis12 complexes to ensure efficient formation of kinetochore-microtubule binding sites. J. Cell Biol. 189, 261–274 (2010).

  159. 159.

    Gurard-Levin, Z. A., Quivy, J. P. & Almouzni, G. Histone chaperones: assisting histone traffic and nucleosome dynamics. Annu. Rev. Biochem. 83, 487–517 (2014).

  160. 160.

    Rosenzweig, R. & Glickman, M. H. Chaperone-driven proteasome assembly. Biochem. Soc. T. 36, 807–812 (2008).

  161. 161.

    Chang, H. C. & Lindquist, S. Conservation of Hsp90 macromolecular complexes in Saccharomyces cerevisiae. J. Biol. Chem. 269, 24983–24988 (1994).

  162. 162.

    Meacham, G. C. et al. Mutations in the yeast Hsp40 chaperone protein Ydj1 cause defects in Axl1 biogenesis and pro-a-factor processing. J. Biol. Chem. 274, 34396–34402 (1999).

  163. 163.

    Dey, B., Caplan, A. J. & Boschelli, F. The Ydj1 molecular chaperone facilitates formation of active p60v-src in yeast. Mol. Biol. Cell 7, 91–100 (1996).

  164. 164.

    Liu, X. D., Morano, K. A. & Thiele, D. J. The yeast Hsp110 family member, SSE1, is an Hsp90 cochaperone. J. Biol. Chem. 274, 26654–26660 (1999).

  165. 165.

    Lamoth, F., Juvvadi, P. R., Soderblom, E. J., Moseley, M. A. & Steinbach, W. J. Hsp70 and the cochaperone StiA (Hop) orchestrate Hsp90-mediated caspofungin tolerance in Aspergillus fumigatus. Antimicrob. Agents Chemother. 59, 4727–4733 (2015).

  166. 166.

    Nathan, D. F. & Lindquist, S. Mutational analysis of Hsp90 function: interactions with a steroid receptor and a protein kinase. Mol. Cell. Biol. 15, 3917–3925 (1995).

  167. 167.

    Piper, P. W. et al. Sensitivity to Hsp90-targeting drugs can arise with mutation to the Hsp90 chaperone, cochaperones and plasma membrane ATP binding cassette transporters of yeast. Eur. J. Biochem. 270, 4689–4695 (2003).

  168. 168.

    Lee, J. R. et al. Heat-shock dependent oligomeric status alters the function of a plant-specific thioredoxin-like protein, AtTDX. Proc. Natl Acad. Sci. USA 106, 5978–5983 (2009).

  169. 169.

    Lee, S. S. et al. Enhancement of chaperone activity of plant-specific thioredoxin through gamma-ray mediated conformational change. Int. J. Mol. Sci. 16, 27302–27312 (2015).

  170. 170.

    Thompson, A. D., Bernard, S. M., Skiniotis, G. & Gestwicki, J. E. Visualization and functional analysis of the oligomeric states of Escherichia coli heat shock protein 70 (Hsp70/DnaK). Cell Stress Chaperones 17, 313–327 (2012).

  171. 171.

    Angelidis, C. E., Lazaridis, I. & Pagoulatos, G. N. Aggregation of hsp70 and hsc70 in vivo is distinct and temperature-dependent and their chaperone function is directly related to non-aggregated forms. Eur. J. Biochem. 259, 505–512 (1999).

  172. 172.

    Araujo, T. L. et al. Conformational changes in human Hsp70 induced by high hydrostatic pressure produce oligomers with ATPase activity but without chaperone activity. Biochemistry 53, 2884–2889 (2014).

  173. 173.

    Freiden, P. J., Gaut, J. R. & Hendershot, L. M. Interconversion of three differentially modified and assembled forms of BiP. EMBO J. 11, 63–70 (1992).

  174. 174.

    Hatayama, T., Yasuda, K. & Yasuda, K. Association of HSP105 with HSC70 in high molecular mass complexes in mouse FM3A cells. Biochem. Biophys. Res. Commun. 248, 395–401 (1998).

  175. 175.

    Bruey, J. M. et al. Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat. Cell Biol. 2, 645–652 (2000).

  176. 176.

    Bruey, J. M. et al. Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo. Oncogene 19, 4855–4863 (2000).

  177. 177.

    Charette, S. J., Lavoie, J. N., Lambert, H. & Landry, J. Inhibition of Daxx-mediated apoptosis by heat shock protein 27. Mol. Cell. Biol. 20, 7602–7612 (2000).

  178. 178.

    Garrido, C. Size matters: of the small HSP27 and its large oligomers. Cell Death Differ. 9, 483–485 (2002).

  179. 179.

    Yonehara, M., Minami, Y., Kawata, Y., Nagai, J. & Yahara, I. Heat-induced chaperone activity of HSP90. J. Biol. Chem. 271, 2641–2645 (1996).

  180. 180.

    Nemoto, T. & Sato, N. Oligomeric forms of the 90-kDa heat shock protein. Biochem. J. 330, 989–995 (1998).

  181. 181.

    Nemoto, T. K., Ono, T. & Tanaka, K. Substrate-binding characteristics of proteins in the 90 kDa heat shock protein family. Biochem. J. 354, 663–670 (2001).

  182. 182.

    Lepvrier, E. et al. Hsp90 oligomers interacting with the Aha1 cochaperone: an outlook for the Hsp90 chaperone machineries. Anal. Chem. 87, 7043–7051 (2015).

  183. 183.

    Lanks, K. W. Temperature-dependent oligomerization of hsp85 in vitro. J. Cell. Physiol. 140, 601–607 (1989).

  184. 184.

    Song, D. et al. Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer. Mol. Cancer Ther. 7, 3275–3284 (2008).

  185. 185.

    Vogen, S. et al. Radicicol-sensitive peptide binding to the N-terminal portion of GRP94. J. Biol. Chem. 277, 40742–40750 (2002).

  186. 186.

    Gaspar, M. E. & Csermely, P. Rigidity and flexibility of biological networks. Brief Funct. Genomics 11, 443–456 (2012).

Download references

Acknowledgements

G.C. is supported by the US National Institutes of Health (NIH) (R01 CA172546, R01 CA155226, P01 CA186866, P30 CA08748 and P50 CA192937), the Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Experimental Therapeutics Center of the Memorial Sloan Kettering Cancer Center; T.W. is supported by the Lymphoma Research Foundation; T.L.S.A. is supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (17/01130-6); and J.L.B. is supported by the Cystic Fibrosis Foundation Therapeutics (BRODSK13XX0) and by the NIH (grants GM75061 and DK79307).

Reviewer information

Nature Reviews Cancer thanks R. Kaufman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Affiliations

  1. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Suhasini Joshi
    • , Tai Wang
    • , Thaís L. S. Araujo
    • , Sahil Sharma
    •  & Gabriela Chiosis
  2. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    • Jeffrey L. Brodsky
  3. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Gabriela Chiosis

Authors

  1. Search for Suhasini Joshi in:

  2. Search for Tai Wang in:

  3. Search for Thaís L. S. Araujo in:

  4. Search for Sahil Sharma in:

  5. Search for Jeffrey L. Brodsky in:

  6. Search for Gabriela Chiosis in:

Contributions

S.J., T.W., T.L.S.A. and S.S. researched data for the article and contributed to the writing of the article and to the review of the manuscript. T.W., T.L.S.A. and G.C. designed the figures and their content. J.L.B. edited the manuscript and provided specific text. G.C. designed the content of the manuscript, researched data for the article and wrote, edited and reviewed the manuscript.

Competing interests

G.C. has partial ownership in Samus Therapeutics Inc., which develops chaperome inhibitors. S.J., T.W., T.L.S.A., S.S. and J.L.B. declare no competing interests.

Corresponding author

Correspondence to Gabriela Chiosis.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/s41568-018-0020-9

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.