Skip to main content
SpringerLink
Log in
Book cover

Molecular Chaperones pp 205–230Cite as

Hsp70: Anti-apoptotic and Tumorigenic Protein

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 787))

Abstract

Heat shock protein 70 (Hsp70) is a powerful chaperone whose expression is induced in response to a wide variety of physiological and environmental insults, including anticancer chemotherapy, thus allowing the cell to survive to lethal conditions. Hsp70 cytoprotective properties may be explained by its anti-apoptotic function. Indeed, this protein can inhibit key effectors of the apoptotic machinery at the pre- and postmitochondrial level. In cancer cells, the expression of Hsp70 is abnormally high, and Hsp70 may participate in oncogenesis and in resistance to chemotherapy. In rodent models, Hsp70 overexpression increases tumor growth and metastatic potential. Depletion or inhibition of Hsp70 frequently reduces the size of the tumors and even can cause their complete involution. But Hsp70 can also be found in the extracellular medium. Its role is then immunogenic and the term chaperokine to define the extracellular chaperones has been advanced. Hsp70 tumorigenic functions as well as the strategies that are being developed in cancer therapy in order to inhibit Hsp70 are commented in this chapter.

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

Protocol
USD   49.95
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

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Ritossa F. A new puffing pattern induced by temperature shock and DNP and in Drosophila. Experientia 1962;18:571–3.

    CAS  Google Scholar 

  2. Tissieres A, Mitchell HK, Tracy UM. Protein synthesis in salivary glands of Drosophila melanogaster: Relation to chromosome puffs. Journal of molecular biology 1974;85(3):389–98.

    Google Scholar 

  3. Li GC, Werb Z. Correlation between synthesis of heat shock proteins and development of thermotolerance in Chinese hamster fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 1982;79(10):3218–22.

    PubMed  CAS  Google Scholar 

  4. Gething MJ, Sambrook J. Protein folding in the cell. Nature 1992;355(6355):33–45.

    PubMed  CAS  Google Scholar 

  5. Feige U, Morimoto RI, Yahara I, Polla BS. Stress-inducible cellular responses. 1996:492p.

    Google Scholar 

  6. Parcellier A, Gurbuxani S, Schmitt E, Solary E, Garrido C. Heat shock proteins, cellular chaperones that modulate mitochondrial cell death pathways. Biochemical and biophysical research communications 2003;304(3):505–12.

    PubMed  CAS  Google Scholar 

  7. Nollen EA, Brunsting JF, Roelofsen H, Weber LA, Kampinga HH. In vivo chaperone activity of heat shock protein 70 and thermotolerance. Mol Cell Biol 1999;19(3):2069–79.

    PubMed  CAS  Google Scholar 

  8. Polla BS, Kantengwa S, Francois D, et al. Mitochondria are selective targets for the protective effects of heat shock against oxidative injury. Proc Natl Acad Sci USA 1996;93(13):6458–63.

    PubMed  CAS  Google Scholar 

  9. Park HS, Cho SG, Kim CK, et al. Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1. Mol Cell Biol 2002;22(22):7721–30.

    PubMed  CAS  Google Scholar 

  10. Garrido C, Gurbuxani S, Ravagnan L, Kroemer G. Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem Biophys Res Commun 2001;286(3):433–42.

    PubMed  CAS  Google Scholar 

  11. Qian SB, McDonough H, Boellmann F, Cyr DM, Patterson C. CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature 2006;440(7083):551–5.

    PubMed  CAS  Google Scholar 

  12. Zermati Y, Garrido C, Amsellem S, et al. Caspase activation is required for terminal erythroid differentiation. J Exp Med 2001;193(2):247–54.

    PubMed  CAS  Google Scholar 

  13. Ribeil JA, Zermati Y, Vandekerckhove J, et al. Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1. Nature 2007;445(7123):102–5.

    PubMed  CAS  Google Scholar 

  14. Jaattela M. Escaping cell death: survival proteins in cancer. Exp Cell Res 1999;248(1):30–43.

    PubMed  CAS  Google Scholar 

  15. Jaattela M. Heat shock proteins as cellular lifeguards. Ann Med 1999;31(4):261–71.

    PubMed  CAS  Google Scholar 

  16. Tavaria M, Gabriele T, Kola I, Anderson RL. A hitchhiker’s guide to the human Hsp70 family. Cell Stress Chaperones 1996;1(1):23–8.

    PubMed  CAS  Google Scholar 

  17. Daugaard M, Rohde M, Jaattela M. The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions. FEBS Lett 2007;581(19):3702–10.

    PubMed  CAS  Google Scholar 

  18. Beckmann RP, Mizzen LE, Welch WJ. Interaction of Hsp 70 with newly synthesized proteins: implications for protein folding and assembly. Science 1990;248(4957):850–4.

    PubMed  CAS  Google Scholar 

  19. Murakami H, Pain D, Blobel G. 70-kD heat shock-related protein is one of at least two distinct cytosolic factors stimulating protein import into mitochondria. J Cell Biol 1988;107(6 Pt 1):2051–7.

    PubMed  CAS  Google Scholar 

  20. Shi Y, Thomas JO. The transport of proteins into the nucleus requires the 70-kilodalton heat shock protein or its cytosolic cognate. Mol Cell Biol 1992;12(5):2186–92.

    PubMed  CAS  Google Scholar 

  21. Vogel M, Bukau B, Mayer MP. Allosteric regulation of Hsp70 chaperones by a proline switch. Mol Cell 2006;21(3):359–67.

    PubMed  CAS  Google Scholar 

  22. Hennessy F, Nicoll WS, Zimmermann R, Cheetham ME, Blatch GL. Not all J domains are created equal: implications for the specificity of Hsp40-Hsp70 interactions. Protein Sci 2005;14(7):1697–709.

    PubMed  CAS  Google Scholar 

  23. Young JC, Agashe VR, Siegers K, Hartl FU. Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 2004;5(10):781–91.

    PubMed  CAS  Google Scholar 

  24. Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell 2006;125(3):443–51.

    PubMed  CAS  Google Scholar 

  25. Voos W. A new connection: chaperones meet a mitochondrial receptor. Mol Cell 2003;11(1):1–3.

    PubMed  CAS  Google Scholar 

  26. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26(4):239–57.

    PubMed  CAS  Google Scholar 

  27. Baehrecke EH. How death shapes life during development. Nat Rev Mol Cell Biol 2002;3(10):779–87.

    PubMed  CAS  Google Scholar 

  28. Solary E, Droin N, Bettaieb A, Corcos L, Dimanche-Boitrel MT, Garrido C. Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies. Leukemia 2000;14(10):1833–49.

    PubMed  CAS  Google Scholar 

  29. Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci 1997;22(8):299–306.

    PubMed  CAS  Google Scholar 

  30. Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 1999;68:383–424.

    PubMed  CAS  Google Scholar 

  31. Kaufmann S. The Intrinsic Pathway of Apoptosis. Apoptosis, Senescence, and Cancer 2007:3–30.

    Google Scholar 

  32. Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001;292(5517):727–30.

    PubMed  CAS  Google Scholar 

  33. Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 2001;15(12):1481–6.

    PubMed  CAS  Google Scholar 

  34. Breckenridge DG, Xue D. Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases. Curr Opin Cell Biol 2004;16(6):647–52.

    PubMed  CAS  Google Scholar 

  35. Cheng EH, Wei MC, Weiler S, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 2001;8(3):705–11.

    PubMed  CAS  Google Scholar 

  36. Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91(4):479–89.

    PubMed  CAS  Google Scholar 

  37. Zhivotovsky B, Orrenius S, Brustugun OT, Doskeland SO. Injected cytochrome c induces apoptosis. Nature 1998;391(6666):449–50.

    PubMed  CAS  Google Scholar 

  38. Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000;102(1):33–42.

    PubMed  CAS  Google Scholar 

  39. Verhagen AM, Silke J, Ekert PG, et al. HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. The Journal of biological chemistry 2002;277(1):445–54.

    PubMed  CAS  Google Scholar 

  40. Verhagen AM, Vaux DL. Cell death regulation by the mammalian IAP antagonist Diablo/Smac. Apoptosis 2002;7(2):163–6.

    PubMed  CAS  Google Scholar 

  41. Creagh EM, Murphy BM, Duriez PJ, Duckett CS, Martin SJ. Smac/Diablo antagonizes ubiquitin ligase activity of inhibitor of apoptosis proteins. The Journal of biological chemistry 2004;279(26):26906–14.

    PubMed  CAS  Google Scholar 

  42. Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S, Peter ME. Apoptosis signaling by death receptors. Eur J Biochem 1998;254(3):439–59.

    PubMed  CAS  Google Scholar 

  43. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998;94(4):481–90.

    PubMed  CAS  Google Scholar 

  44. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998;94(4):491–501.

    PubMed  CAS  Google Scholar 

  45. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G. Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell cycle (Georgetown, Tex 2006;5(22):2592–601.

    Google Scholar 

  46. Mosser DD, Caron AW, Bourget L, et al. The chaperone function of hsp70 is required for protection against stress-induced apoptosis. Mol Cell Biol 2000;20(19):7146–59.

    PubMed  CAS  Google Scholar 

  47. Mosser DD, Morimoto RI. Molecular chaperones and the stress of oncogenesis. Oncogene 2004;23(16):2907–18.

    PubMed  CAS  Google Scholar 

  48. Aghdassi A, Phillips P, Dudeja V, et al. Heat shock protein 70 increases tumorigenicity and inhibits apoptosis in pancreatic adenocarcinoma. Cancer Res 2007;67(2):616–25.

    PubMed  CAS  Google Scholar 

  49. Gurbuxani S, Bruey JM, Fromentin A, et al. Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells. Oncogene 2001;20(51):7478–85.

    PubMed  CAS  Google Scholar 

  50. Nylandsted J, Rohde M, Brand K, Bastholm L, Elling F, Jaattela M. Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc Natl Acad Sci USA 2000;97(14):7871–6.

    PubMed  CAS  Google Scholar 

  51. Schmitt E, Parcellier A, Gurbuxani S, et al. Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis-inducing factor mutant. Cancer Res 2003;63(23):8233–40.

    PubMed  CAS  Google Scholar 

  52. Dix DJ, Allen JW, Collins BW, et al. Targeted gene disruption of Hsp70-2 results in failed meiosis, germ cell apoptosis, and male infertility. Proc Natl Acad Sci USA 1996;93(8):3264–8.

    PubMed  CAS  Google Scholar 

  53. Biggs WH, 3rd, Meisenhelder J, Hunter T, Cavenee WK, Arden KC. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci USA 1999;96(13):7421–6.

    PubMed  CAS  Google Scholar 

  54. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 1999;401(6748):82–5.

    PubMed  CAS  Google Scholar 

  55. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91(2):231–41.

    PubMed  CAS  Google Scholar 

  56. Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998;282(5392):1318–21.

    PubMed  CAS  Google Scholar 

  57. Gao T, Newton AC. The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C. J Biol Chem 2002;277(35):31585–92.

    PubMed  CAS  Google Scholar 

  58. Hu G, Tang J, Zhang B, et al. A novel endothelial-specific heat shock protein HspA12B is required in both zebrafish development and endothelial functions in vitro. J Cell Sci 2006;119(Pt 19):4117–26.

    PubMed  CAS  Google Scholar 

  59. Meriin AB, Yaglom JA, Gabai VL, et al. Protein-damaging stresses activate c-Jun N-terminal kinase via inhibition of its dephosphorylation: a novel pathway controlled by HSP72. Mol Cell Biol 1999;19(4):2547–55.

    PubMed  CAS  Google Scholar 

  60. Park HS, Lee JS, Huh SH, Seo JS, Choi EJ. Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. Embo J 2001;20(3):446–56.

    PubMed  CAS  Google Scholar 

  61. Lee JS, Lee JJ, Seo JS. HSP70 deficiency results in activation of c-Jun N-terminal Kinase, extracellular signal-regulated kinase, and caspase-3 in hyperosmolarity-induced apoptosis. J Biol Chem 2005;280(8):6634–41.

    PubMed  CAS  Google Scholar 

  62. Salehi AH, Morris SJ, Ho WC, et al. AEG3482 is an antiapoptotic compound that inhibits Jun kinase activity and cell death through induced expression of heat shock protein 70. Chem Biol 2006;13(2):213–23.

    PubMed  CAS  Google Scholar 

  63. Gabai VL, Yaglom JA, Volloch V, et al. Hsp72-mediated suppression of c-Jun N-terminal kinase is implicated in development of tolerance to caspase-independent cell death. Mol Cell Biol 2000;20(18):6826–36.

    PubMed  CAS  Google Scholar 

  64. Akakura S, Yoshida M, Yoneda Y, Horinouchi S. A role for Hsc70 in regulating nucleocytoplasmic transport of a temperature-sensitive p53 (p53Val-135). J Biol Chem 2001;276(18):14649–57.

    PubMed  CAS  Google Scholar 

  65. Zylicz M, King FW, Wawrzynow A. Hsp70 interactions with the p53 tumour suppressor protein. Embo J 2001;20(17):4634–8.

    PubMed  CAS  Google Scholar 

  66. Asea A, Rehli M, Kabingu E, et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 2002;277(17):15028–34.

    PubMed  CAS  Google Scholar 

  67. Mijatovic T, Mathieu V, Gaussin JF, et al. Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human non-small cell lung cancers. Neoplasia 2006;8(5):402–12.

    PubMed  CAS  Google Scholar 

  68. Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C. Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol 2007;81(1):15–27.

    PubMed  CAS  Google Scholar 

  69. Ran R, Lu A, Zhang L, et al. Hsp70 promotes TNF-mediated apoptosis by binding IKK gamma and impairing NF-kappa B survival signaling. Genes Dev 2004;18(12):1466–81.

    PubMed  CAS  Google Scholar 

  70. Shanley TP, Ryan MA, Eaves-Pyles T, Wong HR. Heat shock inhibits phosphorylation of I-kappaBalpha. Shock 2000;14(4):447–50.

    PubMed  CAS  Google Scholar 

  71. Yoo CG, Lee S, Lee CT, Kim YW, Han SK, Shim YS. Anti-inflammatory effect of heat shock protein induction is related to stabilization of I kappa B alpha through preventing I kappa B kinase activation in respiratory epithelial cells. J Immunol 2000;164(10):5416–23.

    PubMed  CAS  Google Scholar 

  72. Feng X, Bonni S, Riabowol K. HSP70 induction by ING proteins sensitizes cells to tumor necrosis factor alpha receptor-mediated apoptosis. Mol Cell Biol 2006;26(24):9244–55.

    PubMed  CAS  Google Scholar 

  73. Stankiewicz AR, Lachapelle G, Foo CP, Radicioni SM, Mosser DD. Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J Biol Chem 2005;280(46):38729–39.

    PubMed  CAS  Google Scholar 

  74. Ruchalski K, Mao H, Li Z, et al. Distinct hsp70 domains mediate apoptosis-inducing factor release and nuclear accumulation. J Biol Chem 2006;281(12):7873–80.

    PubMed  CAS  Google Scholar 

  75. Castellino F, Boucher PE, Eichelberg K, et al. Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways. J Exp Med 2000;191(11):1957–64.

    PubMed  CAS  Google Scholar 

  76. Beere HM, Wolf BB, Cain K, et al. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2000;2(8):469–75.

    PubMed  CAS  Google Scholar 

  77. Pandey P, Saleh A, Nakazawa A, et al. Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. The EMBO journal 2000;19(16):4310–22.

    PubMed  CAS  Google Scholar 

  78. Jaattela M, Wissing D, Kokholm K, Kallunki T, Egeblad M. Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. Embo J 1998;17(21):6124–34.

    PubMed  CAS  Google Scholar 

  79. Sakahira H, Nagata S. Co-translational folding of caspase-activated DNase with Hsp70, Hsp40, and inhibitor of caspase-activated DNase. J Biol Chem 2002;277(5):3364–70.

    PubMed  CAS  Google Scholar 

  80. Liu QL, Kishi H, Ohtsuka K, Muraguchi A. Heat shock protein 70 binds caspase-activated DNase and enhances its activity in TCR-stimulated T cells. Blood 2003;102(5):1788–96.

    PubMed  CAS  Google Scholar 

  81. Duriez PJ, Shah GM. Cleavage of poly(ADP-ribose) polymerase: a sensitive parameter to study cell death. Biochem Cell Biol 1997;75(4):337–49.

    PubMed  CAS  Google Scholar 

  82. Decker P, Muller S. Modulating poly (ADP-ribose) polymerase activity: potential for the prevention and therapy of pathogenic situations involving DNA damage and oxidative stress. Curr Pharm Biotechnol 2002;3(3):275–83.

    PubMed  CAS  Google Scholar 

  83. Kotoglou P, Kalaitzakis A, Vezyraki P, et al. Hsp70 translocates to the nuclei and nucleoli, binds to XRCC1 and PARP-1, and protects HeLa cells from single-strand DNA breaks. Cell Stress Chaperones 2009;14(4):391–406.

    PubMed  CAS  Google Scholar 

  84. Gabai VL, Mabuchi K, Mosser DD, Sherman MY. Hsp72 and stress kinase c-jun N-terminal kinase regulate the bid-dependent pathway in tumor necrosis factor-induced apoptosis. Mol Cell Biol 2002;22(10):3415–24.

    PubMed  CAS  Google Scholar 

  85. Pang Q, Keeble W, Christianson TA, Faulkner GR, Bagby GC. FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity. Embo J 2001;20(16):4478–89.

    PubMed  CAS  Google Scholar 

  86. Pang Q, Christianson TA, Keeble W, Koretsky T, Bagby GC. The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC. J Biol Chem 2002;277(51):49638–43.

    PubMed  CAS  Google Scholar 

  87. Guo F, Sigua C, Bali P, et al. Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood 2005;105(3):1246–55.

    PubMed  CAS  Google Scholar 

  88. Schett G, Steiner CW, Groger M, et al. Activation of Fas inhibits heat-induced activation of HSF1 and up-regulation of hsp70. Faseb J 1999;13(8):833–42.

    PubMed  CAS  Google Scholar 

  89. Liossis SN, Ding XZ, Kiang JG, Tsokos GC. Overexpression of the heat shock protein 70 enhances the TCR/CD3- and Fas/Apo-1/CD95-mediated apoptotic cell death in Jurkat T cells. J Immunol 1997;158(12):5668–75.

    PubMed  CAS  Google Scholar 

  90. Cande C, Vahsen N, Garrido C, Kroemer G. Apoptosis-inducing factor (AIF): caspase-independent after all. Cell Death Differ 2004;11(6):591–5.

    PubMed  CAS  Google Scholar 

  91. Creagh EM, Carmody RJ, Cotter TG. Heat shock protein 70 inhibits caspase-dependent and -independent apoptosis in Jurkat T cells. Exp Cell Res 2000;257(1):58–66.

    PubMed  CAS  Google Scholar 

  92. Ravagnan L, Gurbuxani S, Susin SA, et al. Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 2001;3(9):839–43.

    PubMed  CAS  Google Scholar 

  93. Matsumori Y, Hong SM, Aoyama K, et al. Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury. J Cereb Blood Flow Metab 2005;25(7):899–910.

    PubMed  CAS  Google Scholar 

  94. Lui JC, Kong SK. Heat shock protein 70 inhibits the nuclear import of apoptosis-inducing factor to avoid DNA fragmentation in TF-1 cells during erythropoiesis. FEBS Lett 2007;581(1):109–17.

    PubMed  CAS  Google Scholar 

  95. Kalinowska M, Garncarz W, Pietrowska M, Garrard WT, Widlak P. Regulation of the human apoptotic DNase/RNase endonuclease G: involvement of Hsp70 and ATP. Apoptosis 2005;10(4):821–30.

    PubMed  CAS  Google Scholar 

  96. Jaattela M, Tschopp J. Caspase-independent cell death in T lymphocytes. Nat Immunol 2003;4(5):416–23.

    PubMed  Google Scholar 

  97. Guicciardi ME, Deussing J, Miyoshi H, et al. Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J Clin Invest 2000;106(9):1127–37.

    PubMed  CAS  Google Scholar 

  98. Foghsgaard L, Wissing D, Mauch D, et al. Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor. J Cell Biol 2001;153(5):999–1010.

    PubMed  CAS  Google Scholar 

  99. Brunk UT, Svensson I. Oxidative stress, growth factor starvation and Fas activation may all cause apoptosis through lysosomal leak. Redox Rep 1999;4(1–2):3–11.

    PubMed  CAS  Google Scholar 

  100. Broker LE, Huisman C, Span SW, Rodriguez JA, Kruyt FA, Giaccone G. Cathepsin B mediates caspase-independent cell death induced by microtubule stabilizing agents in non-small cell lung cancer cells. Cancer Res 2004;64(1):27–30.

    PubMed  Google Scholar 

  101. Bidere N, Lorenzo HK, Carmona S, et al. Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis. J Biol Chem 2003;278(33):31401–11.

    PubMed  CAS  Google Scholar 

  102. Yuan XM, Li W, Dalen H, et al. Lysosomal destabilization in p53-induced apoptosis. Proc Natl Acad Sci USA 2002;99(9):6286–91.

    PubMed  CAS  Google Scholar 

  103. Brunk UT, Dalen H, Roberg K, Hellquist HB. Photo-oxidative disruption of lysosomal membranes causes apoptosis of cultured human fibroblasts. Free Radic Biol Med 1997;23(4):616–26.

    PubMed  CAS  Google Scholar 

  104. Boya P, Gonzalez-Polo RA, Poncet D, et al. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 2003;22(25):3927–36.

    PubMed  CAS  Google Scholar 

  105. Roberg K, Kagedal K, Ollinger K. Microinjection of cathepsin d induces caspase-dependent apoptosis in fibroblasts. Am J Pathol 2002;161(1):89–96.

    PubMed  CAS  Google Scholar 

  106. Vancompernolle K, Van Herreweghe F, Pynaert G, et al. Atractyloside-induced release of cathepsin B, a protease with caspase-­processing activity. FEBS Lett 1998;438(3):150–8.

    PubMed  CAS  Google Scholar 

  107. Nylandsted J, Gyrd-Hansen M, Danielewicz A, et al. Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med 2004;200(4):425–35.

    PubMed  CAS  Google Scholar 

  108. Bivik C, Rosdahl I, Ollinger K. Hsp70 protects against UVB induced apoptosis by preventing release of cathepsins and cytochrome c in human melanocytes. Carcinogenesis 2007;28(3):537–44.

    PubMed  CAS  Google Scholar 

  109. Simon MM, Reikerstorfer A, Schwarz A, et al. Heat shock protein 70 overexpression affects the response to ultraviolet light in murine fibroblasts. Evidence for increased cell viability and suppression of cytokine release. J Clin Invest 1995;95(3):926–33.

    PubMed  CAS  Google Scholar 

  110. Sashchenko LP, Dukhanina EA, Shatalov YV, et al. Cytotoxic T lymphocytes carrying a pattern recognition protein Tag7 can detect evasive, HLA-negative but Hsp70-exposing tumor cells, thereby ensuring FasL/Fas-mediated contact killing. Blood 2007;110(6):1997–2004.

    PubMed  CAS  Google Scholar 

  111. Ciocca DR, Calderwood SK. Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 2005;10(2):86–103.

    PubMed  CAS  Google Scholar 

  112. Abe M, Manola JB, Oh WK, et al. Plasma levels of heat shock protein 70 in patients with prostate cancer: a potential biomarker for prostate cancer. Clin Prostate Cancer 2004;3(1):49–53.

    PubMed  CAS  Google Scholar 

  113. Ray S, Lu Y, Kaufmann SH, et al. Genomic mechanisms of p210BCR-ABL signaling: induction of heat shock protein 70 through the GATA response element confers resistance to paclitaxel-induced apoptosis. J Biol Chem 2004;279(34):35604–15.

    PubMed  CAS  Google Scholar 

  114. Pocaly M, Lagarde V, Etienne G, et al. Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia. Leukemia 2007;21(1):93–101.

    PubMed  CAS  Google Scholar 

  115. Targosz A, Pierzchalski P, Krawiec A, et al. Helicobacter pylori inhibits expression of heat shock protein 70 (HSP70) in human epithelial cell line. Importance of Cag A protein. J Physiol Pharmacol 2006;57(2):265–78.

    PubMed  CAS  Google Scholar 

  116. Vargas-Roig LM, Gago FE, Tello O, Aznar JC, Ciocca DR. Heat shock protein expression and drug resistance in breast cancer patients treated with induction chemotherapy. Int J Cancer 1998;79(5):468–75.

    PubMed  CAS  Google Scholar 

  117. Brondani Da Rocha A, Regner A, Grivicich I, et al. Radioresistance is associated to increased Hsp70 content in human glioblastoma cell lines. Int J Oncol 2004;25(3):777–85.

    Google Scholar 

  118. Seoane JM, Varela-Centelles PI, Ramirez JR, Cameselle-Teijeiro J, Romero MA, Aguirre JM. Heat shock proteins (HSP70 and HSP27) as markers of epithelial dysplasia in oral leukoplakia. Am J Dermatopathol 2006;28(5):417–22.

    PubMed  Google Scholar 

  119. Takashima M, Kuramitsu Y, Yokoyama Y, et al. Proteomic analysis of autoantibodies in patients with hepatocellular carcinoma. Proteomics 2006;6(13):3894–900.

    PubMed  CAS  Google Scholar 

  120. Jaattela M. Over-expression of hsp70 confers tumorigenicity to mouse fibrosarcoma cells. Int J Cancer 1995;60(5):689–93.

    PubMed  CAS  Google Scholar 

  121. Westerheide SD, Kawahara TL, Orton K, Morimoto RI. Triptolide, an inhibitor of the human heat shock response that enhances stress-induced cell death. J Biol Chem 2006;281(14):9616–22.

    PubMed  CAS  Google Scholar 

  122. Phillips PA, Dudeja V, McCarroll JA, et al. Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res 2007;67(19):9407–16.

    PubMed  CAS  Google Scholar 

  123. Antonoff MB, Chugh R, Borja-Cacho D, et al. Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo. Surgery 2009;146(2):282–90.

    PubMed  Google Scholar 

  124. Bae JH, Kim JY, Kim MJ, et al. Quercetin enhances susceptibility to NK cell-mediated lysis of tumor cells through induction of NKG2D ligands and suppression of HSP70. J Immunother 2010;33(4):391–401.

    PubMed  CAS  Google Scholar 

  125. Li M, Wang J, Jing J, et al. Synergistic promotion of breast cancer cells death by targeting molecular chaperone GRP78 and heat shock protein 70. J Cell Mol Med 2009;13(11–12):4540–50.

    PubMed  CAS  Google Scholar 

  126. Gong Z, Yang J, Yang M, et al. Benzo(a)pyrene inhibits expression of inducible heat shock protein 70 in vascular endothelial cells. Toxicol Lett 2006;166(3):229–36.

    PubMed  CAS  Google Scholar 

  127. Banerjee Mustafi S, Chakraborty PK, Raha S. Modulation of Akt and ERK1/2 pathways by resveratrol in chronic myelogenous leukemia (CML) cells results in the downregulation of Hsp70. PLoS One 2010;5(1):e8719.

    Google Scholar 

  128. Gurbuxani S, Schmitt E, Cande C, et al. Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 2003;22(43):6669–78.

    PubMed  CAS  Google Scholar 

  129. Schmitt E, Maingret L, Puig PE, et al. Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma. Cancer Res 2006;66(8):4191–7.

    PubMed  CAS  Google Scholar 

  130. Leu JI, Pimkina J, Frank A, Murphy ME, George DL. A small molecule inhibitor of inducible heat shock protein 70. Mol Cell 2009;36(1):15–27.

    PubMed  CAS  Google Scholar 

  131. Steele AJ, Prentice AG, Hoffbrand AV, et al. 2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells. Blood 2009;114(6):1217–25.

    PubMed  CAS  Google Scholar 

  132. Williamson DS, Borgognoni J, Clay A, et al. Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. Journal of medicinal chemistry 2009;52(6):1510–3.

    PubMed  CAS  Google Scholar 

  133. Massey AJ, Williamson DS, Browne H, et al. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 2009.

    Google Scholar 

  134. Jinwal UK, Miyata Y, Koren J, 3 rd, et al. Chemical manipulation of hsp70 ATPase activity regulates tau stability. J Neurosci 2009;29(39):12079–88.

    PubMed  CAS  Google Scholar 

  135. Deocaris CC, Widodo N, Shrestha BG, et al. Mortalin sensitizes human cancer cells to MKT-077-induced senescence. Cancer letters 2007;252(2):259–69.

    PubMed  CAS  Google Scholar 

  136. Evans CG, Wisen S, Gestwicki JE. Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1–42) aggregation in vitro. The Journal of biological chemistry 2006;281(44):33182–91.

    PubMed  CAS  Google Scholar 

  137. Wright CM, Seguin SP, Fewell SW, et al. Inhibition of Simian Virus 40 replication by targeting the molecular chaperone function and ATPase activity of T antigen. Virus research 2009;141(1):71–80.

    PubMed  CAS  Google Scholar 

  138. Yi F, Regan L. A novel class of small molecule inhibitors of Hsp90. ACS chemical biology 2008;3(10):645–54.

    PubMed  CAS  Google Scholar 

  139. Roodveldt C, Bertoncini CW, Andersson A, et al. Chaperone proteostasis in Parkinson’s disease: stabilization of the Hsp70/alpha-synuclein complex by Hip. The EMBO journal 2009;28(23):3758–70.

    PubMed  CAS  Google Scholar 

  140. Chang YS, Lee LC, Sun FC, Chao CC, Fu HW, Lai YK. Involvement of calcium in the differential induction of heat shock protein 70 by heat shock protein 90 inhibitors, geldanamycin and radicicol, in human non-small cell lung cancer H460 cells. J Cell Biochem 2006;97(1):156–65.

    PubMed  CAS  Google Scholar 

  141. Yun CH, Yoon SY, Nguyen TT, et al. Geldanamycin inhibits TGF-beta signaling through induction of Hsp70. Archives of biochemistry and biophysics 2010;495(1):8–13.

    PubMed  CAS  Google Scholar 

  142. Powers MV, Clarke PA, Workman P. Death by chaperone: HSP90, HSP70 or both? Cell cycle (Georgetown, Tex 2009;8(4):518–26.

    Google Scholar 

  143. Powers MV, Clarke PA, Workman P. Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis. Cancer Cell 2008;14(3):250–62.

    PubMed  CAS  Google Scholar 

  144. Chalmin F, Ladoire S, Mignot G, et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. The Journal of clinical investigation 2010;120(2):457–71.

    PubMed  CAS  Google Scholar 

  145. Asea A, Kabingu E, Stevenson MA, Calderwood SK. HSP70 peptidembearing and peptide-negative preparations act as chaperokines. Cell Stress Chaperones 2000;5(5):425–31.

    PubMed  CAS  Google Scholar 

  146. Bausero MA, Page DT, Osinaga E, Asea A. Surface expression of Hsp25 and Hsp72 differentially regulates tumor growth and metastasis. Tumour Biol 2004;25(5–6):243–51.

    PubMed  CAS  Google Scholar 

  147. Bausero MA, Gastpar R, Multhoff G, Asea A. Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J Immunol 2005;175(5):2900–12.

    PubMed  CAS  Google Scholar 

  148. Shin BK, Wang H, Yim AM, et al. Global profiling of the cell surface proteome of cancer cells uncovers an abundance of proteins with chaperone function. J Biol Chem 2003;278(9):7607–16.

    PubMed  CAS  Google Scholar 

  149. Arispe N, Doh M, Simakova O, Kurganov B, De Maio A. Hsc70 and Hsp70 interact with phosphatidylserine on the surface of PC12 cells resulting in a decrease of viability. Faseb J 2004;18(14):1636–45.

    PubMed  CAS  Google Scholar 

  150. Schilling D, Gehrmann M, Steinem C, et al. Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells. Faseb J 2009;23(8):2467–77.

    PubMed  CAS  Google Scholar 

  151. Asea A. Mechanisms of HSP72 release. J Biosci 2007;32(3):579–84.

    PubMed  CAS  Google Scholar 

  152. Mambula SS, Calderwood SK. Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol 2006;177(11):7849–57.

    PubMed  CAS  Google Scholar 

  153. Vega VL, Rodriguez-Silva M, Frey T, et al. Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol 2008;180(6):4299–307.

    PubMed  CAS  Google Scholar 

  154. Srivastava P. Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2002;2(3):185–94.

    PubMed  CAS  Google Scholar 

  155. Nicchitta CV. Re-evaluating the role of heat-shock protein-peptide interactions in tumour immunity. Nat Rev Immunol 2003;3(5):427–32.

    PubMed  CAS  Google Scholar 

  156. Udono H, Srivastava PK. Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med 1993;178(4):1391–6.

    PubMed  CAS  Google Scholar 

  157. Asea A, Kraeft SK, Kurt-Jones EA, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000;6(4):435–42.

    PubMed  CAS  Google Scholar 

  158. Kuppner MC, Gastpar R, Gelwer S, et al. The role of heat shock protein (hsp70) in dendritic cell maturation: hsp70 induces the maturation of immature dendritic cells but reduces DC differentiation from monocyte precursors. Eur J Immunol 2001;31(5):1602–9.

    PubMed  CAS  Google Scholar 

  159. Multhoff G, Botzler C, Jennen L, Schmidt J, Ellwart J, Issels R. Heat shock protein 72 on tumor cells: a recognition structure for natural killer cells. J Immunol 1997;158(9):4341–50.

    PubMed  CAS  Google Scholar 

  160. Todryk SM, Melcher AA, Dalgleish AG, Vile RG. Heat shock proteins refine the danger theory. Immunology 2000;99(3):334–7.

    PubMed  CAS  Google Scholar 

  161. Castelli C, Rivoltini L, Rini F, et al. Heat shock proteins: biological functions and clinical application as personalized vaccines for human cancer. Cancer Immunol Immunother 2004;53(3):227–33.

    PubMed  CAS  Google Scholar 

  162. Arnold-Schild D, Hanau D, Spehner D, et al. Cutting edge: receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells. J Immunol 1999;162(7):3757–60.

    PubMed  CAS  Google Scholar 

  163. Basu S, Binder RJ, Ramalingam T, Srivastava PK. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 2001;14(3):303–13.

    PubMed  CAS  Google Scholar 

  164. Binder RJ, Han DK, Srivastava PK. CD91: a receptor for heat shock protein gp96. Nat Immunol 2000;1(2):151–5.

    PubMed  CAS  Google Scholar 

  165. Binder RJ, Vatner R, Srivastava P. The heat-shock protein receptors: some answers and more questions. Tissue Antigens 2004;64(4):442–51.

    PubMed  CAS  Google Scholar 

  166. Sondermann H, Becker T, Mayhew M, Wieland F, Hartl FU. Characterization of a receptor for heat shock protein 70 on macrophages and monocytes. Biol Chem 2000;381(12):1165–74.

    PubMed  CAS  Google Scholar 

  167. Binder RJ, Blachere NE, Srivastava PK. Heat shock protein-chaperoned peptides but not free peptides introduced into the cytosol are presented efficiently by major histocompatibility complex I molecules. J Biol Chem 2001;276(20):17163–71.

    PubMed  CAS  Google Scholar 

  168. Doody AD, Kovalchin JT, Mihalyo MA, Hagymasi AT, Drake CG, Adler AJ. Glycoprotein 96 can chaperone both MHC class I- and class II-restricted epitopes for in vivo presentation, but selectively primes CD8+ T cell effector function. J Immunol 2004;172(10):6087–92.

    PubMed  CAS  Google Scholar 

  169. Schild H, Arnold-Schild D, Lammert E, Rammensee HG. Stress proteins and immunity mediated by cytotoxic T lymphocytes. Curr Opin Immunol 1999;11(1):109–13.

    PubMed  CAS  Google Scholar 

  170. Singh-Jasuja H, Toes RE, Spee P, et al. Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis. J Exp Med 2000;191(11):1965–74.

    PubMed  CAS  Google Scholar 

  171. Srivastava PK, Menoret A, Basu S, Binder RJ, McQuade KL. Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world. Immunity 1998;8(6):657–65.

    PubMed  CAS  Google Scholar 

  172. Wells AD, Malkovsky M. Heat shock proteins, tumor immunogenicity and antigen presentation: an integrated view. Immunol Today 2000;21(3):129–32.

    PubMed  CAS  Google Scholar 

  173. Flechtner JB, Cohane KP, Mehta S, et al. High-affinity interactions between peptides and heat shock protein 70 augment CD8+ T lymphocyte immune responses. J Immunol 2006;177(2):1017–27.

    PubMed  CAS  Google Scholar 

  174. Habich C, Baumgart K, Kolb H, Burkart V. The receptor for heat shock protein 60 on macrophages is saturable, specific, and distinct from receptors for other heat shock proteins. J Immunol 2002;168(2):569–76.

    PubMed  CAS  Google Scholar 

  175. Vabulas RM, Ahmad-Nejad P, da Costa C, et al. Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem 2001;276(33):31332–9.

    PubMed  CAS  Google Scholar 

  176. Bendz H, Ruhland SC, Pandya MJ, et al. Human heat shock protein 70 enhances tumor antigen presentation through complex formation and intracellular antigen delivery without innate immune signaling. J Biol Chem 2007;282(43):31688–702.

    PubMed  CAS  Google Scholar 

  177. Haug M, Schepp CP, Kalbacher H, Dannecker GE, Holzer U. 70-kDa heat shock proteins: specific interactions with HLA-DR molecules and their peptide fragments. Eur J Immunol 2007;37(4):1053–63.

    PubMed  CAS  Google Scholar 

  178. Matzinger P. The danger model: a renewed sense of self. Science 2002;296(5566):301–5.

    PubMed  CAS  Google Scholar 

  179. Zhang H, Huang W. Fusion proteins of Hsp70 with tumor-associated antigen acting as a potent tumor vaccine and the C-terminal peptide-binding domain of Hsp70 being essential in inducing antigen-independent anti-tumor response in vivo. Cell Stress Chaperones 2006;11(3):216–26.

    PubMed  CAS  Google Scholar 

  180. Sanchez-Perez L, Kottke T, Daniels GA, et al. Killing of normal melanocytes, combined with heat shock protein 70 and CD40L expression, cures large established melanomas. J Immunol 2006;177(6):4168–77.

    PubMed  CAS  Google Scholar 

  181. Gao B, Tsan MF. Recombinant human heat shock protein 60 does not induce the release of tumor necrosis factor alpha from murine macrophages. J Biol Chem 2003;278(25):22523–9.

    PubMed  CAS  Google Scholar 

  182. Reed RC, Berwin B, Baker JP, Nicchitta CV. GRP94/gp96 elicits ERK activation in murine macrophages. A role for endotoxin contamination in NF-kappa B activation and nitric oxide production. J Biol Chem 2003;278(34):31853–60.

    PubMed  CAS  Google Scholar 

  183. Suto R, Srivastava PK. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 1995;269(5230):1585–8.

    PubMed  CAS  Google Scholar 

  184. Janetzki S, Palla D, Rosenhauer V, Lochs H, Lewis JJ, Srivastava PK. Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: a pilot study. Int J Cancer 2000;88(2):232–8.

    PubMed  CAS  Google Scholar 

  185. Kottke T, Sanchez-Perez L, Diaz RM, et al. Induction of hsp70-mediated Th17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer. Cancer Res 2007;67(24):11970–9.

    PubMed  CAS  Google Scholar 

  186. Jimbo J, Sato K, Hosoki T, et al. Induction of leukemia-specific antibodies by immunotherapy with leukemia-cell-derived heat shock protein 70. Cancer Sci 2008;99(7):1427–34.

    PubMed  CAS  Google Scholar 

  187. Toomey D, Conroy H, Jarnicki AG, Higgins SC, Sutton C, Mills KH. Therapeutic vaccination with dendritic cells pulsed with tumor-derived Hsp70 and a COX-2 inhibitor induces protective immunity against B16 melanoma. Vaccine 2008;26(27–28):3540–9.

    PubMed  CAS  Google Scholar 

  188. Mizukami S, Kajiwara C, Ishikawa H, Katayama I, Yui K, Udono H. Both CD4+ and CD8+ T cell epitopes fused to heat shock cognate protein 70 (hsc70) can function to eradicate tumors. Cancer Sci 2008;99(5):1008–15.

    PubMed  CAS  Google Scholar 

  189. Liu B, Ye D, Song X, et al. A novel therapeutic fusion protein vaccine by two different families of heat shock proteins linked with HPV16 E7 generates potent antitumor immunity and antiangiogenesis. Vaccine 2008;26(10):1387–96.

    PubMed  CAS  Google Scholar 

  190. Enomoto Y, Bharti A, Khaleque AA, et al. Enhanced immunogenicity of heat shock protein 70 peptide complexes from dendritic cell-tumor fusion cells. J Immunol 2006;177(9):5946–55.

    PubMed  CAS  Google Scholar 

  191. Ciocca DR, Frayssinet P, Cuello-Carrion FD. A pilot study with a therapeutic vaccine based on hydroxyapatite ceramic particles and self-antigens in cancer patients. Cell Stress Chaperones 2007;12(1):33–43.

    PubMed  CAS  Google Scholar 

  192. Zeng Y, Chen X, Larmonier N, et al. Natural killer cells play a key role in the antitumor immunity generated by chaperone-rich cell lysate vaccination. Int J Cancer 2006;119(11):2624–31.

    PubMed  CAS  Google Scholar 

  193. Gross C, Hansch D, Gastpar R, Multhoff G. Interaction of heat shock protein 70 peptide with NK cells involves the NK receptor CD94. Biol Chem 2003;384(2):267–79.

    PubMed  CAS  Google Scholar 

  194. Gross C, Schmidt-Wolf IG, Nagaraj S, et al. Heat shock protein 70-reactivity is associated with increased cell surface density of CD94/CD56 on primary natural killer cells. Cell Stress Chaperones 2003;8(4):348–60.

    PubMed  CAS  Google Scholar 

  195. Botzler C, Li G, Issels RD, Multhoff G. Definition of extracellular localized epitopes of Hsp70 involved in an NK immune response. Cell Stress Chaperones 1998;3(1):6–11.

    PubMed  CAS  Google Scholar 

  196. Multhoff G, Mizzen L, Winchester CC, et al. Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells. Exp Hematol 1999;27(11):1627–36.

    PubMed  CAS  Google Scholar 

  197. Gastpar R, Gehrmann M, Bausero MA, et al. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 2005;65(12):5238–47.

    PubMed  CAS  Google Scholar 

  198. Stangl S, Wortmann A, Guertler U, Multhoff G. Control of metastasized pancreatic carcinomas in SCID/beige mice with human IL-2/TKD-activated NK cells. J Immunol 2006;176(10):6270–6.

    PubMed  CAS  Google Scholar 

  199. Krause SW, Gastpar R, Andreesen R, et al. Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: a clinical phase i trial. Clin Cancer Res 2004;10(11):3699–707.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the “Ligue Nationale Contre le Cancer” and the committees form the “Nièvre” and “Saône et Loire.” CG’s group has the label de “La Ligue Contre le Cancer.” The work was also supported by grants from the “Institut National du Cancer” and “Conseil Regional de Bourgogne.”

Author information

Authors and Affiliations

  1. Faculty of Medicine and Pharmacy, INSERM, U-866, Dijon, France

    Anne-Laure Rérole, Gaëtan Jego & Carmen Garrido

Authors
  1. Anne-Laure Rérole
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gaëtan Jego
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carmen Garrido
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carmen Garrido .

Editor information

Editors and Affiliations

  1. Beth Israel Deaconess Medical Center, Department of Radiation Oncology, Harvard Medical School, Brookline Ave 330, Boston, 02215, Massachusetts, USA

    Stuart K. Calderwood

  2. National Cancer Institute, Urologic Oncology Branch, National Institutes of Health, Rockville Pike 9000, Bethesda, 20814, Maryland, USA

    Thomas L. Prince

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Rérole, AL., Jego, G., Garrido, C. (2011). Hsp70: Anti-apoptotic and Tumorigenic Protein. In: Calderwood, S., Prince, T. (eds) Molecular Chaperones. Methods in Molecular Biology, vol 787. Humana Press. https://doi.org/10.1007/978-1-61779-295-3_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-295-3_16

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-61779-294-6

  • Online ISBN: 978-1-61779-295-3

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation