Hsp60 Involvement During Carcinogenesis

  • Francesca Rappa
  • Francesco Carini
  • Pierre Schembri Wismayer
Part of the Heat Shock Proteins book series (HESP, volume 18)


The implication of Hsp60 in cancer development is due to its participation in many metabolic and biomolecular mechanisms in cancer cells. Hsp60 interacts with various molecules that are responsible of apoptosis, cell proliferation and other mechanisms involved when a normal cell becomes malignant. Hsp60 expression was found to be increased in many types of cancer but in same tumors of different anatomical district was found decreased. The mechanism of action of Hsp60 is different depending on the type of tumor. Its involvement in the carcinogenetic process of some tumors, such as large bowel carcinoma or cervical carcinoma, seems to occur in the very early stages of disease. Hsp60 participates in the mechanism of modulation of the immune response the cancer cells use to invade surrounding tissues, and expand the tumor mass.


Apoptosis Biomolecular Cancer cell Carcinogenesis Hsp60 Tumor progression 



Antigen-presenting cells


Bcl-2-associated X protein


Cluster of differentiation


Cancer myelocytomatosis


Chronic obstructive pulmonary disease


Dendritic cells


Grading 1


Grading 2


Grading 3


Heat shock protein


Inhibitors of apoptosis protein


Interferon gamma


IκB kinase






Matrix metallopeptidase 9


Mithocondrial Heat shock protein


Myeloid differentiation primary response 88


Human lung mucoepidermoid cell


Nuclear factor kappa-light-chain-enhancer of activated B cells


Natural killer




Prostatic intraepithelial lesions


Reactive oxygen species


Squamous cell carcinomas


Squamous intraepithelial lesion


Type 1 T helper


Toll-like receptor


Vascular endothelial growth factor



F.C. and F.R. were partially supported by UniPA.


  1. Barazi HO, Zhou L, Templeton NS, Krutzsch HC, Roberts DD (2002) Identification of heat shock protein 60 as molecular mediator of alpha 3 beta 1integrin activation. Cancer Res 62:1541–1548PubMedPubMedCentralGoogle Scholar
  2. Cabibi D, Conway de Macario E, Ingrao S et al (2015) CD1a-positive cells and Hsp60 (HSPD1) levels in keratoacantomas and squamous cell carcinoma. Cell Stress Chaperones 21:131–137PubMedPubMedCentralCrossRefGoogle Scholar
  3. Campanella C, Bucchieri F, Ardizzone NM et al (2008) Upon oxidative stress, the antiapoptotic Hsp60/procaspase-3 complex persist in mucoepidermoid carcinoma cells. Eur J Histochem 52:221–228PubMedPubMedCentralCrossRefGoogle Scholar
  4. Campanella C, Bucchieri F, Merendino AM et al (2012) The odyssey of Hsp60 from tumor cells to other destinations includes plasma membrane-associated stages and Golgi and exosomal proteintrafficking modalities. PLoS One 7:e42008PubMedPubMedCentralCrossRefGoogle Scholar
  5. Campanella C, Rappa F, Sciumè C et al (2015) Heat shock protein 60 levels in tissue and circulating exosomes in human large bowel cancer before and after ablative surgery. Cancer 121:3230–3239PubMedPubMedCentralCrossRefGoogle Scholar
  6. Cappello F, Zummo G (2005) HSP60 expression during carcinogenesis: a molecular “Proteus” of carcinogenesis? Cell Stress Chaperones 10:263–264PubMedPubMedCentralCrossRefGoogle Scholar
  7. Cappello F, Bellafiore M, Palma A et al (2002) Expression of 60-kD heat shock protein increases during carcinogenesis in the uterine exocervix. Pathobiology 70:83–88PubMedCrossRefGoogle Scholar
  8. Cappello F, Bellafiore M, David S, Anzalone R, Zummo G (2003a) Ten kilodalton heat shock protein (HSP10) is overexpressed during carcinogenesis of large bowel and uterine exocervix. Cancer Lett 196:35–41PubMedCrossRefGoogle Scholar
  9. Cappello F, Bellafiore M, Palma A et al (2003b) 60kDa chaperonin (HSP60) is overexpressed during colorectal carcinogenesis. Eur J Histochem 47:105–110PubMedCrossRefGoogle Scholar
  10. Cappello F, Rappa F, David S, Anzalone R, Zummo G (2003c) Immunohistochemical evaluation of PCNA, p53, HSP60, HSP10 and MUC-2 presence and expression in prostate carcinogenesis. Anticancer Res 23:1325–1331PubMedGoogle Scholar
  11. Cappello F, David S, Rappa F et al (2005a) The expression of HSP60 and HSP10 in large bowel carcinomas with lymph node metastase. BMC Cancer 5:139PubMedPubMedCentralCrossRefGoogle Scholar
  12. Cappello F, Di Stefano A, D’Anna SE, Donner CF, Zummo G (2005b) Immunopositivity of heat shock protein 60 as a biomarker of bronchial carcinogenesis. Lancet Oncol 6:816PubMedCrossRefGoogle Scholar
  13. Cappello F, David S, Ardizzone N et al (2006a) Expression of heat-shock proteins Hsp10, Hsp27, Hsp60, Hsp70 and Hsp90 in urothelial carcinoma of urinary bladder. J Cancer Mol 2:7Google Scholar
  14. Cappello F, Di Stefano A, David S et al (2006b) Hsp60 and Hsp10 down-regulation predicts bronchial epithelial carcinogenesis in smokers with chronic obstructive pulmonary disease. Cancer 107:2417–2424.3-77PubMedCrossRefGoogle Scholar
  15. Cappello F, David S, Peri G et al (2011) Hsp60: molecular anatomy and role in colorectal cancer diagnosis and treatment. Front Biosci S3:341–351CrossRefGoogle Scholar
  16. Caruso Bavisotto C, Nikolic D, Marino Gammazza A et al (2017) The dissociation of the Hsp60/pro-Caspase-3 complex by bis(pyridyl)oxadiazole copper complex (CubipyOXA) leads to cell death in NCI-H292 cancer cells. J Inorg Biochem 170:8–16PubMedPubMedCentralCrossRefGoogle Scholar
  17. Castilla C, Congregado B, Conde JM et al (2010) Immunohistochemical expression of Hsp60 correlates with tumor progression and hormone resistance in prostate Cancer. Urology 76:1017.e1–1017.e6CrossRefGoogle Scholar
  18. Chandra D, Choy G, Tang DG (2007) Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3. J Biol Chem 282:31289–31301PubMedCrossRefGoogle Scholar
  19. Chandrasekaran L, He CZ, Al-Barzai H, Krutzsch HC, Irulea-Arispe ML, Robets DD (2000) Cell contact-dependent activation of alpha 3 beta 1integrin modulates endothelial cell responses to thrombospondin-1. Mol Biol Cell 11:2885–2900PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chow MT, Möller A, Smyth MJ (2012) Inflammation and immune surveillance in cancer. Semin Cancer Biol 22:23–32PubMedCrossRefGoogle Scholar
  21. Chun JN, Choi B, Lee KW et al (2010) Cytosolic Hsp60 in involved in the NF-kB dependent survival of cancer cell via IKK regulation. PLoS One 5:e9422PubMedPubMedCentralCrossRefGoogle Scholar
  22. Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86–103PubMedPubMedCentralCrossRefGoogle Scholar
  23. Cohen-Sfady M, Nussbaum G, Pevsner-Fischer M et al (2005) Control of B-cell responses by toll-like receptors. Nature 438:364–368CrossRefGoogle Scholar
  24. Corrao S, La Rocca G, Anzalone R et al (2008) Role of CD1a and Hsp60 in the antitumoral response of oesophageal cancer. Oncol Rev 1:225–232CrossRefGoogle Scholar
  25. Coventry BJ, Heinzel S (2004) CD1a in human cancers: a new role for an old molecule. Trends Immunol 25:242–248PubMedCrossRefGoogle Scholar
  26. Di Felice V, David S, Cappello F, Farina F, Zummo G (2005) Is chlamydial heat shock protein 60 a risk factor for oncogenesis? Cell Mol Life Sci 62:4–9PubMedCrossRefGoogle Scholar
  27. Fan GK, Chen F, Gen Y (2006) Immunohistochemical analysis of P57(kip2), p53 and Hsp60 expression in premalignant and malignant oral tissue. Oral Oncol 42:147–153PubMedCrossRefGoogle Scholar
  28. Flohé SB, Brüggermann J, Lendemans S et al (2003) Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype. J Immunol 170:2340–2348PubMedCrossRefGoogle Scholar
  29. Ghosh JC, Dohi T, Kang BH, Altieri DC (2008) Hsp60 regulation of tumor cell apoptosis. J Biol Chem 283:5188–5194CrossRefGoogle Scholar
  30. Gorska M, Marino Gammazza A, Zmijewski MA et al (2013) Geldanamycin-induced osteosarcoma cell death is associated with hyperacetylation and loss of mitochondrial pool of heat shock protein 60 (hsp60). PLoS One 8:e71135PubMedPubMedCentralCrossRefGoogle Scholar
  31. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899PubMedPubMedCentralCrossRefGoogle Scholar
  32. Kao TY, Chiu YC, Fang WC et al (2015) Mitochondrial Lon regulates apoptosis through the association with Hsp60-mtHsp70 complex. Cell Death Dis 6:e1642PubMedPubMedCentralCrossRefGoogle Scholar
  33. Kimura E, Enns RE, Thiebaut F, Howell SB (1993) Regulation of HSP60 mRNA expression in a human ovarian carcinoma cell line. Cancer Chemother Pharmacol 32:279–285PubMedCrossRefGoogle Scholar
  34. Lanneau D, Brunet M, Frisan E, Solary E, Fontenay M, Garrido C (2008) Heat shock proteins: essential proteins for apoptosis regulation. J Cell Mol Med 12:743–761PubMedPubMedCentralCrossRefGoogle Scholar
  35. Lebret T, Watson RW, Molinie V (2003) Heat shock proteins HSP27, HSP60, HSP70, and HSP90: expression in bladder carcinoma. Cancer 98:970–977PubMedCrossRefGoogle Scholar
  36. Li X-s, Xu Q, Fu X-y, Luo W-s (2014) Heat shock protein 60 overexpression is associated with the progression and prognosis in gastric Cancer. PLoS One 9:e107507PubMedPubMedCentralCrossRefGoogle Scholar
  37. Macario AJL, Conway de Macario E (2007) Chaperonopathies by defect, excess, or mistake. Ann N Y Acad Sci 1113:178–191PubMedCrossRefGoogle Scholar
  38. Merendino AM, Bucchieri F, Campanella C et al (2010) Hsp60 is actively secreted by human tumor cells. PLoS One 5:e9247PubMedPubMedCentralCrossRefGoogle Scholar
  39. Osterloh A, Kalinke U, Weiss S, Fleisher B, Breloer M (2007) Synergistic and differential modulation of immune responses byHSP60 and LPS. J Biol Chem 282:4669–4680PubMedCrossRefGoogle Scholar
  40. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506PubMedPubMedCentralCrossRefGoogle Scholar
  41. Pasare C, Medzhitov R (2005) Control of B-cell responses by Toll-like receptors. Nature 438:364–368PubMedCrossRefGoogle Scholar
  42. Rappa F, Farina F, Zummo G et al (2012) HSP-molecular chaperones in cancer biogenesis and tumor therapy: an overview. Anticancer Res 32:5139–5150PubMedPubMedCentralGoogle Scholar
  43. Rappa F, Unti E, Baiamonte P, Cappello F, Scibetta N (2013) Different immunohistochemical levels of Hsp60 and Hsp70 in a subset of brain tumors and putative role of Hsp60 in neuroepithelial tumorigenesis. Eur J Histochem 57:e20PubMedPubMedCentralCrossRefGoogle Scholar
  44. Rappa F, Pitruzzella A, Marino Gammazza A et al (2016) Quantitative patterns of Hsps in tubular adenoma compared with normal and tumoral tissue, reveal the value of Hsp10 and Hsp60 in early diagnosis of large bowel cancer. Cell Stress Chaperones 21:927–933PubMedPubMedCentralCrossRefGoogle Scholar
  45. Samali A, Cai J, Zhivotovsky B, Jones DP, Orrenius S (1999) Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of Jurkat cells. EMBO J 18:2040–2048PubMedPubMedCentralCrossRefGoogle Scholar
  46. Schneider J, Jiménez E, Marenbach K, Romero H, Marx D, Meden H (1999) Immunohistochemical detection of HSP60 expression in human ovarian cancer. Correlation with survival in a series of 247 patients. Anticancer Res 19:2141–2146PubMedGoogle Scholar
  47. Tsai YP, Yang MH, Huang CH et al (2009) Interaction between HSP60 and βcatenin promotes metastasis. Carcinogenesis 30:1049–1057PubMedCrossRefGoogle Scholar
  48. Xanthoudakis S, Roy S, Rasper D et al (1999) Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. EMBO J 18:2049–2056PubMedPubMedCentralCrossRefGoogle Scholar
  49. Zanin-Zhorov A, Nussbaum G, Franitza S, Cohen IR, Lider O (2003) T cells respond to heat shock protein 60 via TRL2: activation of adhesion and inhibition of chemokine receptors. FASEB J 17:1567–1569PubMedCrossRefGoogle Scholar
  50. Zanin-Zhorov A, Tal G, Shivtiel S et al (2005) Heat shock protein 60 activates cytokineassociated negative regulator suppressor of cytokine signaling 3 in T cells: effects on signaling, chemotaxis, and inflammation. J Immunol 175:276–285PubMedCrossRefGoogle Scholar
  51. Zhang D, Fei F, Li S et al (2017) The role of βcatenin in the initiation and metastasis of TA2 mice spontaneous breast cancer. J Cancer 8:2114–2123PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Francesca Rappa
    • 1
  • Francesco Carini
    • 1
  • Pierre Schembri Wismayer
    • 2
  1. 1.Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), Section of Human AnatomyUniversity of PalermoPalermoItaly
  2. 2.Department of Anatomy, Centre for Molecular Medicine and Biobanking, Faculty of Medicine and SurgeryUniversity of MaltaMsidaMalta

Personalised recommendations