Heat Shock Protein 27: Structure, Function, Cellular Role and Inhibitors

Part of the Topics in Medicinal Chemistry book series (TMC, volume 19)


Hsp27 is an important heat shock protein found in all organisms from prokaryotes to mammals. It is a structurally conserved ATP-independent protein, present in both normal and abnormal tissues. Its expression and induction occur under stressed conditions. The self-association to form oligomers and subsequent equilibrium between oligomer and dimer play critical roles in regulating Hsp27’s function. Site-specific phosphorylation of Hsp27 regulates this equilibrium, controlling the activity of Hsp27. Hsp27’s molecular chaperone activity includes interacting with a large number of proteins and regulating their folding states. Significant levels of Hsp27 expression have been observed in many diseases, including cancer, neuronal diseases and cardiac diseases. Herein we describe the current understanding of Hsp27’s structure, function, cellular role and inhibitors.


ATP independent Cancer Heat shock proteins Hsp27 Natural products Small molecules 


  1. 1.
    Concannon CG, Gorman AM, Samali A (2003) On the role of Hsp27 in regulating apoptosis. Apoptosis 8:61–70. doi: 10.1023/A:1021601103096 CrossRefGoogle Scholar
  2. 2.
    Ciocca DR, Adams DJ, Edwards DP, Bjercke RJ, McGuire WL (1983) Distribution of an estrogen-induced protein with a molecular weight of 24,000 in normal and malignant human tissues and cells. Cancer Res 43:1204–1210Google Scholar
  3. 3.
    Hickey E, Brandon SE, Potter R, Stein G, Stein J, Weber LA (1986) Sequence and organization of genes encoding the human 27 kDa heat shock protein. Nucleic Acids Res 14:4127–4145CrossRefGoogle Scholar
  4. 4.
    Sun Y, MacRae TH (2005) Small heat shock proteins: molecular structure and chaperone function. Cell Mol Life Sci 62:2460–2476Google Scholar
  5. 5.
    Jovcevski B, Kelly M, Rote A, Berg T, Gastall HY, Benesch J, Aquilina JA, Ecroyd H (2015) Phosphomimics destabilize Hsp27 oligomeric assemblies and enhance chaperone activity. Chem Bio 22:186–195CrossRefGoogle Scholar
  6. 6.
    Horwitz J (1992) Alpha-crystallin can function as a molecular chaperone. Proc Natl Acad Sci USA 89:10449–10453CrossRefGoogle Scholar
  7. 7.
    Pauli D, Tonka CH, Tissieres A, Arrigo AP (1990) Tissue-specific expression of the heat shock protein HSP27 during Drosophila melanogaster development. J Cell Biol 111:817–828. doi: 10.1083/jcb.111.3.817 CrossRefGoogle Scholar
  8. 8.
    Hastie AT, Everts KB, Zangrilli J, Shaver JR, Pollice MB, Fish JE, Peters SP (1997) HSP27 elevated in mild allergic inflammation protects airway epithelium from H2SO4 effects. J Physiol Lung Cell Mol Physiol 273:L401–L409Google Scholar
  9. 9.
    Lebherz-Eichinger D, Ankersmit JH, Hacker S, Hetz H, Kimberger O, Schmidt ME, Reiter T, Horl HW, Haas M, Krenn GC, Roth AG (2012) HSP27 and HSP70 serum and urine levels in patients suffering from chronic kidney disease. Clin Chim Acta 413:282–286CrossRefGoogle Scholar
  10. 10.
    Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, Abbruzzese JL, Hortobagyi GN, Hung MC (2007) Epidermal growth factor receptor cooperates with signal transducer and activator of transcription to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res 67:9066–9076CrossRefGoogle Scholar
  11. 11.
    McConnell JP, McAlpine SR (2013) Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. Bioorg Med Chem Lett 23:1923–1928CrossRefGoogle Scholar
  12. 12.
    Vander Heide RS (2002) Increased expression of HSP27 protects canine myocytes from simulated ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 282:H935–H941. doi: 10.1152/ajpheart.00660.2001 CrossRefGoogle Scholar
  13. 13.
    Yang C, Wang H, Zhu D, Hong CS, Dmitriev P, Zhang C, Li Y, Ikejiri B, Brady RO, Zhuang Z (2015) Mutant glucocerebrosidase in Gaucher disease recruits Hsp27 to the Hsp90 chaperone complex for proteasomal degradation. Proc Natl Acad Sci U S A 112:1137–1142CrossRefGoogle Scholar
  14. 14.
    Mendillo ML, Santagata S, Koeva M, Bell GW, Hu R, Tamimi RM, Fraenkel E, Ince TA, Whitesell L, Lindquist S (2012) HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell 150:549–562Google Scholar
  15. 15.
    Santagata S, Hu R, Lin NU, Mendillo ML, Collins LC, Hankinson SE, Schnitt JS, Whitesell L, Tamimi RL, Lindquist S, Ince TA (2011) High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. PNAS 108:18378–18383CrossRefGoogle Scholar
  16. 16.
    Whitesell L, Lindquist S (2009) Inhibiting the transcription factor HSF1 as an anticancer strategy. Expert Opin Ther Targets 13:469–478CrossRefGoogle Scholar
  17. 17.
    Lelj-Garolla B, Mauk AG (2012) Roles of the N- and C-terminal sequences in Hsp27 self-association and chaperone activity. Protein Sci 21:122–133CrossRefGoogle Scholar
  18. 18.
    Lambert H, Charette JS, Bernier FZ, A G, Landry J (1999) Hsp27 multimerization mediated by phosphorylation-sensitive intermolecular interactions at the amino terminus. J Biol Chem 14:9378–9385Google Scholar
  19. 19.
    Hayes D, Napoli V, Mazurkie A, Stafford FW, Graceffa P (2009) Phosphorylation dependence of Hsp27 multimeric size and molecular chaperone function. J Biol Chem 284:18801–18807CrossRefGoogle Scholar
  20. 20.
    McDonald ET, Bortolus M, Koteiche HA, Mchaourab HS (2012) Sequence, structure, and dynamic determinants of Hsp27 (HspB1) equilibrium dissociation are encoded by the N-terminal domain. Biochemistry 51:1257–1268CrossRefGoogle Scholar
  21. 21.
    Rogalla T, Ehrnsperger M, Preville X, Kotlyarov A, Lutsch G, Ducasse C, Paul C, Wieske M, Arrigo AP, Buchner J, Gaestel M (1999) Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor α by phosphorylation. J Biol Chem 274:18947–18956CrossRefGoogle Scholar
  22. 22.
    Shashidharamurthy R, Koteiche HA, Dong J, McHaourab HS (2005) Mechanism of chaperone function in small heat shock proteins: dissociation of the HSP27 oligomer is required for recognition and binding of destabilized T4 lysozyme. J Biol Chem 280:5281–5289CrossRefGoogle Scholar
  23. 23.
    Baranova EV, Weeks SD, Beelen S, Bukach OV, Gusev NB, Strelkov SV (2011) Three-dimensional structure of α-crystallin domain dimers of human small heat shock proteins HSPB1 and HSPB6. J Mol Biol 411:110–122CrossRefGoogle Scholar
  24. 24.
    Wang X, Chen M, Zhou J, Zhang X (2014) HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy (review). Int J Oncol 45:18–30Google Scholar
  25. 25.
    Hessling M, Richter K, Buchner J (2009) Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90. Nat Struct Mol Biol 16:287–293CrossRefGoogle Scholar
  26. 26.
    Li J, Soroka J, Buchner J (2012) The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim Biophys Acta 1832:624–635CrossRefGoogle Scholar
  27. 27.
    Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516CrossRefGoogle Scholar
  28. 28.
    Guay J, Lambert H, Gingras-Breton G, Lavoie JN, Huot J, Landry J (1997) Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. J Cell Sci 110:357–368Google Scholar
  29. 29.
    Lavoie JN, Hickey E, Weber LA, Landry J (1993) Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27. J Biol Chern 268:3420–3429Google Scholar
  30. 30.
    Dominguez R, Holmes KC (2011) Actin structure and function. Ann Rev Biophys 40:169–186CrossRefGoogle Scholar
  31. 31.
    Gorman AM, Heavey B, Creagh E, Cotter TG, Samali A (1999) Antioxidant-mediated inhibition of the heat shock response leads to apoptosis. FEBS Lett 445:98–102Google Scholar
  32. 32.
    Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Mitsiades N, Catley L, Tai YT, Hayashi T, Shringarpure R, Burger R, Munshi N, Ohtake Y, Saxena S, Anderson KC (2003) Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance. Blood 102:3379–3386CrossRefGoogle Scholar
  33. 33.
    Samali A, Robertson JD, Peterson E, Manero F, Van Zeijl L, Paul C, Cotgreave IA, Arrigo AP, Orrenius S (2001) Hsp27 protects mitochondria of thermotolerant cells against apoptotic stimuli. Cell Stress Chaperones 6:49–58CrossRefGoogle Scholar
  34. 34.
    O’Neill PA, Shaaban AM, West CR, Dodson A, Jarvis C, Moore P, Davies MP, Sibson DR, Foster CS (2004) Increased risk of malignant progression in benign proliferating breast lesions defined by expression of heat shock protein 27. Br J Cancer 90:182–188CrossRefGoogle Scholar
  35. 35.
    Kang SH, Kang KW, Kim KH, Kwon B, Kim SK, Lee HY, Kong SY, Lee ES, Jang SG, Yoo BG (2008) Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability. BMC Cancer 8(286)Google Scholar
  36. 36.
    Cornford PA, Dodson AR, Parsons KF, Desmond AD, Woolfenden A, Fordham M, Neoptolemos JP, Ke Y, Foster CS (2000) Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res 60:7099–7105Google Scholar
  37. 37.
    Shiota M, Bishop JL, KM N, Zardan A, Takeuchi A, Cordonnier T, Beraldi E, Bazov J, Fazli L, Chi K, Gleave M, Zoubeidi A (2013) Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer Res 73:3109–3119Google Scholar
  38. 38.
    Marinova DM, Slavova YG, Trifonova N, Kostadinov D, Maksimov V, Petrov D (2013) Stress protein Hsp27 expression predicts the outcome in operated small cell lung carcinoma and large cell neuroendocrine carcinoma patients. JBUON 18(4):915–920Google Scholar
  39. 39.
    Oba M, Yano S, Shuto T, Suico AM, Euma A, Kai H (2008) IFN-γ down-regulates Hsp27 expression and enhance hyperthermia-induced tumor cell death in vitro and tumor suppression in vivo. Int J Oncol 32:1317–1324Google Scholar
  40. 40.
    Wua J, Jianga S, Ding Z, Liu L (2013) Role of heat shock protein 27 in cardiovascular disease. J Biochem Pharmacol Res 1:43–50Google Scholar
  41. 41.
    Jin C, Phillips VL, Williams MJ, Van Rij AM, Jones GT (2014) Plasma heat shock protein 27 is associated with coronary artery disease, abdominal aortic aneurysm and peripheral artery disease. SpringerPlus 3(635)Google Scholar
  42. 42.
    Zhang X, Min X, Li C, Benjamin JI, Qian BI, Zhang X, Ding Z, Gao X, Yao Y, Ma Y, Cheng Y, Liu L (2010) Involvement of reductive stress in the cardiomyopathy in transgenic mice with cardiac-specific overexpression of heat shock protein 27. Hypertension 55:1412–1417CrossRefGoogle Scholar
  43. 43.
    Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366CrossRefGoogle Scholar
  44. 44.
    Dobson CM (2001) The structural basis of protein folding and its links with human disease. Philos Trans R Soc Lond B Biol Sci 356:133–145CrossRefGoogle Scholar
  45. 45.
    Muchowski PJ, Wacker JLW (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22CrossRefGoogle Scholar
  46. 46.
    Shimura H, Miura-Shimura Y, Kosik KS (2004) Binding of tau to heat shock protein 27 leads to decreased concentration of hyper-phosphorylated tau and enhanced cell survival. J Biol Chem 279:17957–17962CrossRefGoogle Scholar
  47. 47.
    Perrin V, Regulier E, Abbas-Terki T, Hassig R, Brouillet E, Aebischer P, Luthi-Carter R, Deglon N (2007) Neuroprotection by Hsp104 and Hsp27 in lentiviral-based rat models of Huntington’s disease. Mol Ther 15:903–911CrossRefGoogle Scholar
  48. 48.
    Baylot V, Andrieu C, Katsogiannou M, Taieb D, Garcia S, Giusiano S, Acunzo J, Iovanna J, Gleave M, Garrido C, Rocchi P (2011) OGX-427 inhibits tumor progression and enhances gemcitabine chemotherapy in pancreatic cancer. Cell Death Dis 2(e221)Google Scholar
  49. 49.
    Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811CrossRefGoogle Scholar
  50. 50.
    Liu XX, Rocchi P, Qu FQ, Zheng SQ, Liang ZC, Gleave M, Iovanna J, Peng L (2009) PAMAM dendrimers mediate siRNA delivery to target Hsp27 and produce potent antiproliferative effects on prostate cancer cells. ChemMedChem 4:1302–1310CrossRefGoogle Scholar
  51. 51.
    Heinrich JC, Tuukkanen A, Schroeder M, Fahrig T, Fahrig R (2011) RP101 (brivudine) binds to heat shock protein Hsp27 (HSPB1) and enhances survival in animals and pancreatic cancer patients. J Cancer Res Clin Oncol 137:1349–1361CrossRefGoogle Scholar
  52. 52.
    Shin KD, Yoon YJ, Kang YR, Son KH, Kim HM, Kwon BM, Han DC (2008) KRIBB3, a novel microtubule inhibitor, induces mitotic arrest and apoptosis in human cancer cells. Biochem Pharmacol 75:383–394CrossRefGoogle Scholar
  53. 53.
    Di Carlo G, Mascolo N, lzzo AA, Capasso F (1999) Flavonoids: old and new aspects of a class of natural therapeutic drugs. Life Sci 65:337–353Google Scholar
  54. 54.
    Rusznyak S, Szent-Gyorgyi A (1936) Vitamin P: flavonols as vitamins. Nature 136:27CrossRefGoogle Scholar
  55. 55.
    Peterson J, Dwyer J (1998) Flavonoids: dietary occurrence and biochemical activity. Nutr Res 18:1995–1998CrossRefGoogle Scholar
  56. 56.
    Rossi M, Rickles LF, Halpin WA (1986) The crystal and molecular structure of quercetin: a biologically active and naturally occurring flavonoid. Bioorg Chem 14:55–69CrossRefGoogle Scholar
  57. 57.
    Maalik A, Khan FA, Mumtaz A, Mehmood A, Azhar S, Atif M, Karim S, Altaf Y, Tariq I (2014) Pharmacological applications of quercetin and its derivatives: a short review. Trop J Pharm Res 13:1561–1566CrossRefGoogle Scholar
  58. 58.
    Boumendjel A, Di Pietro A, Dumontet C, Barron D (2002) Recent advances in the discovery of flavonoids and analogs with high-affinity binding to P-Glycoprotein responsible for cancer cell multidrug resistance. Med Res Rev 22:512–529CrossRefGoogle Scholar
  59. 59.
    Materska M (2008) Quercetin and its derivatives: chemical structure and bioactivity-a review. Pol J Food Nutr Sci 58:407–413Google Scholar
  60. 60.
    Nijveldt RJ, Van Nood E, Van Hoorn DE, Boelens PG, Van Norren K, Van Leeuwen PA (2001) Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 74:418–425Google Scholar
  61. 61.
    Pratheeshkumar P, Sreekala C, Zhang Z, Budhraja A, Ding S, Son YO, Wang X, Hitron A, Hyun-Jung K, Wang L, Lee JC, Shi X (2012) Cancer prevention with promising natural products: mechanisms of action and molecular targets. Anticancer Agents Med Chem 12:1159–1184CrossRefGoogle Scholar
  62. 62.
    Afpinasev IB, Dokozhko AI, Brodakii AV, Kostyuk VA, Potapovitchs AI (1989) Chelating and free radical scavenging mechanisms of inhibitory action of Rutin and Quercetin in lipid peroxidation. Biochem Pharmacol 38:1763–1769CrossRefGoogle Scholar
  63. 63.
    Fotsis T, Pepper MS, Aktas E, Breit S, Rasku S, Adlercreutz H, Wahala K, Montesano R, Schweigerer L (1997) Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res 57:2916–2921Google Scholar
  64. 64.
    Hou DX, Kumamoto T (2010) Flavonoids as protein kinase inhibitors for cancer chemoprevention: direct binding and molecular modeling. Antioxid Redox Signal 13:691–719CrossRefGoogle Scholar
  65. 65.
    Russo M, Palumbo R, Mupo A, Tosto M, Iacomino G, Scognamiglio A, Tedesco I, Galano G, Russo GL (2003) Flavonoid quercetin sensitizes a CD95-resistant cell line to apoptosis by activating protein kinase. Oncogene 22:3330–3342CrossRefGoogle Scholar
  66. 66.
    Hosokawa N, Hirayoshi K, Nakai A, Hosokawa Y, Marui N, Yoshida M, Sakai T, Nishino H, Aoike A, Kawai K, Nagata K (1990) Flavonoids inhibit the expression of heat shock proteins. Cell Struct Funct 15:393–401CrossRefGoogle Scholar
  67. 67.
    Elia G, Santoro MG (1994) Regulation of heat shock protein synthesis by quercetin in human erythroleukaemia cells. J Biochem 300:201–209CrossRefGoogle Scholar
  68. 68.
    Chen SF, Nieh S, Jao SW, Liu CL, Wu CH, Chang YC, Yang CY, Lin YS (2012) Quercetin suppresses drug-resistant spheres via the p38 MAPK–Hsp27 apoptotic pathway in oral cancer cells. PLoS One 7, e49275CrossRefGoogle Scholar
  69. 69.
    Badziul D, Jakubowicz-Gil J, Paduch R, Głowniak K, Gawron A (2014) Combined treatment with quercetin and imperatorin as a potent strategy for killing HeLa and Hep-2 cells. Mol Cell Biochem 392:213–227CrossRefGoogle Scholar
  70. 70.
    Gibert B, Hadchity E, Czekalla A, Aloy MT, Colas P, Rodriguez-Lafrasse C, Arrigo AP, Diaz-Latoud C (2011) Inhibition of heat shock protein 27 (HspB1) tumorigenic functions by peptide aptamers. Oncogene 30:3672–3681CrossRefGoogle Scholar
  71. 71.
    Fanelli MA, Cuello Carrion FD, Dekker J, Schoemaker J, Ciocca DR (1998) Serological detection of heat shock protein Hsp27 in normal and breast cancer patients. Cancer Epidemiol Biomarkers Prev 7:791–795Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Faculty of Science, School of Chemistry KensingtonUniversity of New South WalesSydneyAustralia

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