Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Molecular Chaperones and How Addiction Matters in Cancer Therapy

  • Chapter
  • First Online:
Cell Death Signaling in Cancer Biology and Treatment

Part of the book series: Cell Death in Biology and Diseases ((CELLDEATH))

Abstract

Constitutive expression of HSP90 in normal cells is required for its evolutionarily conserved housekeeping function of folding and translocating cellular proteins to their proper cellular compartment. Under the stress of malignant transformation, cellular proteins and networks become perturbed requiring specific maintenance by a stress-modified HSP90. We here detail the many functions this oncogenic HSP90 takes on in cancer cells and discuss how the addiction of cancer-altered networks on HSP90 can be harvested therapeutically by small molecule HSP90 inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674 (Epub 2011/03/08)

    Google Scholar 

  2. Nahleh Z, Tfayli A, Najm A, El Sayed A, Nahle Z (2012) Heat shock proteins in cancer: targeting the chaperones. Future Med Chem 4(7):927–935 (Epub 2012/05/11)

    Google Scholar 

  3. Khalil AA, Kabapy NF, Deraz SF, Smith C (2011) Heat shock proteins in oncology: diagnostic biomarkers or therapeutic targets? Biochim Biophys 1816(2):89–104 (Epub 2011/05/25)

    Google Scholar 

  4. Calderwood SK (2010) Heat shock proteins in breast cancer progression–a suitable case for treatment? Int J Hyperth: official J Eur Soc Hyperth Oncol, North American Hyperthermia Group 26(7):681–685 (Epub 2010/07/27)

    Google Scholar 

  5. Soo ET, Yip GW, Lwin ZM, Kumar SD, Bay BH (2008) Heat shock proteins as novel therapeutic targets in cancer. In vivo 22(3):311–315 (Epub 2008/07/10)

    Google Scholar 

  6. Johnson JL (2012) Evolution and function of diverse Hsp90 homologs and cochaperone proteins. Biochim Biophys 1823(3):607–613 (Epub 2011/10/20)

    Google Scholar 

  7. Cotto JJ, Morimoto RI (1999) Stress-induced activation of the heat-shock response: cell and molecular biology of heat-shock factors. Biochem Soc Symp 64:105–118 (Epub 1999/04/20)

    Google Scholar 

  8. Solimini NL, Luo J, Elledge SJ (2007) Non-oncogene addiction and the stress phenotype of cancer cells. Cell 130(6):986–988 (Epub 2007/09/25)

    Google Scholar 

  9. Jego G, Hazoume A, Seigneuric R, Garrido C (2010) Targeting heat shock proteins in cancer. Cancer Lett Epub (2010/11/17)

    Google Scholar 

  10. Patel HJ, Modi S, Chiosis G, Taldone T (2011) Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment. Expert Opin Drug Discov 6(5):559–587 (Epub 2012/03/09)

    Google Scholar 

  11. Prodromou C, Roe SM, O’Brien R, Ladbury JE, Piper PW, Pearl LH (1997) Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90(1):65–75 (Epub 1997/07/11)

    Google Scholar 

  12. Sorger PK, Pelham HRB (1987) The glucose-regulated protein grp94 is related to heat shock protein hsp90. J Mol Biol 194(2):341–344

    Article  CAS  PubMed  Google Scholar 

  13. Altieri DC, Stein GS, Lian JB, Languino LR (2012) TRAP-1, the mitochondrial Hsp90. Biochim Biophys 1823(3):767–773 (Epub 2011/09/01)

    Google Scholar 

  14. Sreedhar AS, Kalmar E, Csermely P, Shen YF (2004) Hsp90 isoforms: functions, expression and clinical importance. FEBS Lett 562(1–3):11–15 (Epub 2004/04/09)

    Google Scholar 

  15. da Silva VC, Ramos CH (2012) The network interaction of the human cytosolic 90 kDa heat shock protein Hsp90: A target for cancer therapeutics. J Proteomics 75(10):2790–2802 (Epub 2012/01/13)

    Google Scholar 

  16. Chene P (2002) ATPases as drug targets: learning from their structure. Nat Rev Drug Discov 1(9):665–673 (Epub 2002/09/05)

    Google Scholar 

  17. Pearl LH, Prodromou C (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271–294 (Epub 2006/06/08)

    Google Scholar 

  18. Prodromou C (2012) The active life of Hsp90 complexes. Biochim Biophys 1823(3):614–623 (Epub 2011/08/16)

    Google Scholar 

  19. Pearl LH, Prodromou C, Workman P (2008) The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem J 410(3):439–453 (Epub 2008/02/23)

    Google Scholar 

  20. Jhaveri K, Taldone T, Modi S, Chiosis G (2012) Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys 1823(3):742–755 (Epub 2011/11/09)

    Google Scholar 

  21. Travers J, Sharp S, Workman P (2012) HSP90 inhibition: two-pronged exploitation of cancer dependencies. Drug Discovery Today 17(5–6):242–252 (Epub 2012/01/17)

    Google Scholar 

  22. Neckers L (2006) Using natural product inhibitors to validate Hsp90 as a molecular target in cancer. Curr Top Med Chem 6(11):1163–1171 (Epub 2006/07/18)

    Google Scholar 

  23. Voss AK, Thomas T, Gruss P (2000) Mice lacking HSP90beta fail to develop a placental labyrinth. Development 127(1):1–11 (Epub 2000/02/02)

    Google Scholar 

  24. Ross JS, Schenkein DP, Pietrusko R, Rolfe M, Linette GP, Stec J et al (2004) Targeted therapies for cancer 2004. Am J Clin pathol 122(4):598–609 (Epub 2004/10/19)

    Google Scholar 

  25. Neckers L, Schulte TW, Mimnaugh E (1999) Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest New Drugs 17(4):361–373 (Epub 2000/04/12)

    Google Scholar 

  26. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC et al (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425(6956):407–410 (Epub 2003/09/26)

    Google Scholar 

  27. Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DaGama EM et al (2011) Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat Chem Biol 7(11):818–826 (Epub 2011/09/29)

    Google Scholar 

  28. Workman P, Burrows F, Neckers L, Rosen N (2007) Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci 1113:202–216 (Epub 2007/05/22)

    Google Scholar 

  29. Makhnevych T, Houry WA (2012) The role of Hsp90 in protein complex assembly. Biochim Biophys 1823(3):674–682 (Epub 2011/09/29)

    Google Scholar 

  30. Walter S, Buchner J (2002) Molecular chaperones–cellular machines for protein folding. Angewandte Chemie 41(7):1098–1113 (Epub 2002/12/20)

    Google Scholar 

  31. Young JC, Moarefi I, Hartl FU (2001) Hsp90: a specialized but essential protein-folding tool. J Cell Biol 154(2):267–273 (Epub 2001/07/27)

    Google Scholar 

  32. Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5(10):761–772 (Epub 2005/09/22)

    Google Scholar 

  33. Perdew GH, Whitelaw ML (1991) Evidence that the 90-kDa heat shock protein (HSP90) exists in cytosol in heteromeric complexes containing HSP70 and three other proteins with Mr of 63,000, 56,000, and 50,000. J Biol Chem 266(11):6708–6713 (Epub 1991/04/15)

    Google Scholar 

  34. Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Nat Acad Sci U. S. A. 91(18):8324–8328 (Epub 1994/08/30)

    Google Scholar 

  35. Blagosklonny MV, Toretsky J, Neckers L (1995) Geldanamycin selectively destabilizes and conformationally alters mutated p53. Oncogene 11(5):933–939 (Epub 1995/09/07)

    Google Scholar 

  36. Grbovic OM, Basso AD, Sawai A, Ye Q, Friedlander P, Solit D et al (2006) V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc Nat Acad Sci U. S. A. 103(1):57–62 (Epub 2005/12/24)

    Google Scholar 

  37. Pratt WB, Galigniana MD, Morishima Y, Murphy PJ (2004) Role of molecular chaperones in steroid receptor action. Essays Biochem 40:41–58 (Epub 2004/07/10)

    Google Scholar 

  38. Pratt WB, Toft DO (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocrine Rev 18(3):306–360 (Epub 1997/06/01)

    Google Scholar 

  39. Echeverria PC, Mazaira G, Erlejman A, Gomez-Sanchez C, Piwien Pilipuk G, Galigniana MD (2009) Nuclear import of the glucocorticoid receptor-hsp90 complex through the nuclear pore complex is mediated by its interaction with Nup62 and importin beta. Mol Cell Biol 29(17):4788–4797 (Epub 2009/07/08)

    Google Scholar 

  40. Galigniana MD, Erlejman AG, Monte M, Gomez-Sanchez C, Piwien-Pilipuk G (2010) The hsp90-FKBP52 complex links the mineralocorticoid receptor to motor proteins and persists bound to the receptor in early nuclear events. Mol Cell Biol 30(5):1285–1298 (Epub 2009/12/30)

    Google Scholar 

  41. Conway-Campbell BL, George CL, Pooley JR, Knight DM, Norman MR, Hager GL et al (2011) The HSP90 molecular chaperone cycle regulates cyclical transcriptional dynamics of the glucocorticoid receptor and its coregulatory molecules CBP/p300 during ultradian ligand treatment. Mol Endocrinol 25(6):944–954 (Epub 2011/04/23)

    Google Scholar 

  42. Nagata Y, Anan T, Yoshida T, Mizukami T, Taya Y, Fujiwara T et al (1999) The stabilization mechanism of mutant-type p53 by impaired ubiquitination: the loss of wild-type p53 function and the hsp90 association. Oncogene 18(44):6037–6049 (Epub 1999/11/11)

    Google Scholar 

  43. Peng Y, Chen L, Li C, Lu W, Chen J (2001) Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization. J Biol Chem 276(44):40583–40590 (Epub 2001/08/17)

    Google Scholar 

  44. Lin K, Rockliffe N, Johnson GG, Sherrington PD, Pettitt AR (2008) Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells. Oncogene 27(17):2445–2455 (Epub 2007 Nov 5)

    Google Scholar 

  45. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399(6733):271–275 (Epub 1999/06/03)

    Google Scholar 

  46. Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem 277(33):29936–29944 (Epub 2002/06/08)

    Google Scholar 

  47. Cerchietti LC, Lopes EC, Yang SN, Hatzi K, Bunting KL, Tsikitas LA et al (2009) A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Nat Med 15(12):1369–1376 (Epub 2009/12/08)

    Google Scholar 

  48. Bird A (2001) Molecular biology: Methylation talk between histones and DNA. Science 294(5549):2113–2115 (Epub 2001/12/12)

    Google Scholar 

  49. Zhou Q, Agoston AT, Atadja P, Nelson WG, Davidson NE (2008) Inhibition of histone deacetylases promotes ubiquitin-dependent proteasomal degradation of DNA methyltransferase 1 in human breast cancer cells. Mol Cancer Res: MCR 6(5):873–883 (Epub 2008/05/29)

    Google Scholar 

  50. Fiskus W, Buckley K, Rao R, Mandawat A, Yang Y, Joshi R et al (2009) Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol Ther 8(10):939–950 (Epub 2009/03/13)

    Google Scholar 

  51. Chang CJ, Hung MC (2012) The role of EZH2 in tumour progression. Br J Cancer 106(2):243–247 (Epub 2011/12/22)

    Google Scholar 

  52. He Y, Korboukh I, Jin J, Huang J (2012) Targeting protein lysine methylation and demethylation in cancers. Biochim Biophys Sinica 44(1):70–79 (Epub 2011/12/24)

    Google Scholar 

  53. Ho L, Crabtree GR (2008) An EZ mark to miss. Cell Stem Cell 3(6):577–578 (Epub 2008/12/02)

    Google Scholar 

  54. Fiskus W, Buckley K, Rao R, Mandawat A, Yang Y, Joshi R et al (2009) Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol Ther 8(10):939–950 (Epub 2009/03/13)

    Google Scholar 

  55. Karkhanis V, Hu YJ, Baiocchi RA, Imbalzano AN, Sif S (2011) Versatility of PRMT5-induced methylation in growth control and development. Trends Biochem Sci 36(12):633–641 (Epub 2011/10/07)

    Google Scholar 

  56. Maloney A, Clarke PA, Naaby-Hansen S, Stein R, Koopman JO, Akpan A et al (2007) Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Cancer Res 67(7):3239–3253 (Epub 2007/04/06)

    Google Scholar 

  57. Imhof A (2003) Histone modifications: an assembly line for active chromatin? Curr Biol: CB 13(1):R22–R24 (Epub 2003/01/16)

    Google Scholar 

  58. Kim YR, Lee BK, Park RY, Nguyen NT, Bae JA, Kwon DD et al (2010) Differential CARM1 expression in prostate and colorectal cancers. BMC Cancer 10:197 (Epub 2010/05/14)

    Google Scholar 

  59. Abu-Farha M, Lanouette S, Elisma F, Tremblay V, Butson J, Figeys D et al (2011) Proteomic analyses of the SMYD family interactomes identify HSP90 as a novel target for SMYD2. J Mol cell Biol 3(5):301–308 (Epub 2011/10/27)

    Google Scholar 

  60. Luo XG, Zou JN, Wang SZ, Zhang TC, Xi T (2010) Novobiocin decreases SMYD3 expression and inhibits the migration of MDA-MB-231 human breast cancer cells. IUBMB Life 62(3):194–199 (Epub 2009/12/30)

    Google Scholar 

  61. Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481(7381):287–294 (Epub 2012/01/20)

    Google Scholar 

  62. Samant RS, Clarke PA, Workman P (2012) The expanding proteome of the molecular chaperone HSP90. Cell Cycle 11(7):1301–1308 (Epub 2012/03/17)

    Google Scholar 

  63. Noguchi M, Yu D, Hirayama R, Ninomiya Y, Sekine E, Kubota N et al (2006) Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Biochem Biophys Res Commun 351(3):658–663 (Epub 2006/11/07)

    Google Scholar 

  64. Ha K, Lee GE, Palii SS, Brown KD, Takeda Y, Liu K et al (2011) Rapid and transient recruitment of DNMT1 to DNA double-strand breaks is mediated by its interaction with multiple components of the DNA damage response machinery. Human Mol Genet 20(1):126–40 (Epub 2010/10/14)

    Google Scholar 

  65. Solier S, Kohn KW, Scroggins B, Xu W, Trepel J, Neckers L et al (2012) Feature Article: Heat shock protein 90alpha (HSP90alpha), a substrate and chaperone of DNA-PK necessary for the apoptotic response. Proc Nat Acad Sci U S A (Epub 2012/07/04)

    Google Scholar 

  66. Solier S, Pommier Y (2009) The apoptotic ring: a novel entity with phosphorylated histones H2AX and H2B and activated DNA damage response kinases. Cell Cycle 8(12):1853–1859 (Epub 2009/05/19)

    Google Scholar 

  67. Camphausen K, Tofilon PJ (2007) Inhibition of Hsp90: a multitarget approach to radiosensitization. Clin Cancer Res Official J Am Assoc Cancer Res 13(15 Pt 1):4326–4330 (Epub 2007/08/03)

    Google Scholar 

  68. Stingl L, Niewidok N, Muller N, Selle M, Djuzenova CS, Flentje M (2012) Radiosensitizing effect of the novel Hsp90 inhibitor NVP-AUY922 in human tumour cell lines silenced for Hsp90alpha. Strahlentherapie und Onkologie : Organ Der Deutschen Rontgengesellschaft 188(6):507–515 (Epub 2012/03/24)

    Google Scholar 

  69. Hartson SD, Matts RL (2012) Approaches for defining the Hsp90-dependent proteome. Biochim Biophys 1823(3):656–667 (Epub 2011/09/13)

    Google Scholar 

  70. Zhao R, Davey M, Hsu YC, Kaplanek P, Tong A, Parsons AB et al (2005) Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone. Cell 120(5):715–727 (Epub 2005/03/16)

    Google Scholar 

  71. Sharma K, Vabulas RM, Macek B, Pinkert S, Cox J, Mann M et al (2012) Quantitative proteomics reveals that Hsp90 inhibition preferentially targets kinases and the DNA damage response. Mol Cell Proteomics: MCP 11(3):M111 014654 (Epub 2011/12/15)

    Google Scholar 

  72. Chiosis G, Timaul MN, Lucas B, Munster PN, Zheng FF, Sepp-Lorenzino L et al (2001) A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells. Chem Biol 8(3):289–99 (Epub 2001/04/18)

    Google Scholar 

  73. Trepel J, Mollapour M, Giaccone G, Neckers L (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10(8):537–549 (Epub 2010/07/24)

    Google Scholar 

Download references

Acknowledgments

G Chiosis is funded in part by Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and “The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center”, the Geoffrey Beene Cancer Research Center of MSKCC, Leukemia and Lymphoma Society, Breast Cancer Research Fund, the SPORE Pilot Award and Research and Therapeutics Program in Prostate Cancer, the Hirshberg Foundation for Pancreatic Cancer, the Byrne Fund, National Institutes of Health (1U01 AG032969, 1R01CA155226, 1R21AI090501, 1R21CA158609, 3P30CA008748, P50CA086438), MSKCC Society, Department of Defense (R03-BC085588), Susan G Komen for the Cure and the Institute for the Study of Aging and The Association for Frontotemporal Dementias (Grant #281207 AFTD). T Taldone discloses a grant support from the Department of Defense (PDF-BC093421). M Guzman is funded by the US National Institutes of Health (NIH) through the NIH Director’s New Innovator Award Program, 1 DP2 OD007399-01, National Cancer Institute (R21 CA158728-01A1), Leukemia and Lymphoma Foundation (LLS 6330-11), and she is a V Foundation Scholar.

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Weill Cornell Medical College, NY, USA

    Monica L. Guzman

  2. Department of Medicine, Gastrointestinal Service, Memorial Sloan-Kettering Cancer Center, NY, USA

    Maeve A. Lowery

  3. Department of Medicine, Breast Cancer Service, Memorial Sloan-Kettering Cancer Center, NY, USA

    Tony Taldone, John Koren III, Erica DaGama Gomes & Gabriela Chiosis

  4. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, NY, USA

    Tony Taldone, John Koren III, Erica DaGama Gomes & Gabriela Chiosis

Authors
  1. Monica L. Guzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maeve A. Lowery
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tony Taldone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John Koren III
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erica DaGama Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gabriela Chiosis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabriela Chiosis .

Editor information

Editors and Affiliations

  1. Department of Medicine, University of Pittsburgh Division of Hematology/Oncology, Pittsburgh, Pennsylvania, USA

    Daniel E. Johnson

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Guzman, M.L., Lowery, M.A., Taldone, T., Koren, J., Gomes, E.D., Chiosis, G. (2013). Molecular Chaperones and How Addiction Matters in Cancer Therapy. In: Johnson, D. (eds) Cell Death Signaling in Cancer Biology and Treatment. Cell Death in Biology and Diseases. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-5847-0_7

Download citation

Publish with us

Policies and ethics

Search

Navigation