Hsp60 and Hsp10 as antitumour molecular agents

Cappello, Francesco; Czarnecka, Anna M.; Rocca, Giampiero La; Stefano, Antonino Di; Zummo, Giovanni; Macario, Alberto J. L.

doi:10.4161/cbt.6.4.4087

Cited by 34 publications

(28 citation statements)

References 26 publications

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“…In turn, the former induces cell death, while the latter can lead to the formation of immunoprecipitates in the renal glomeruli for instance [35]. We have previously postulated that if Hsp60 occurs on the surface of malignant cells, as already ascertained for some types of cancer, anti-Hsp60 antibodies have the potential ability to destroy the tumor [29,35,40]. Our hypothesis has been recently supported by observations on multiple myelomas [41].…”

Section: Anti-hsp60 Antibodies: Danger or Safety?supporting

confidence: 66%

Chaperonopathies and Chaperonotherapy. Hsp60 as Therapeutic Target in Cancer: Potential Benefits and Risks

Cappello

Angileri²,

Macario³

et al. 2013

Current Pharmaceutical Design

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Abstract:In this minireview we focus on Hsp60 as a target for anticancer therapy. We discuss the new concepts of chaperonopathies and chaperonotherapy and present information on Hsp60 localization in the cell membrane of human tumor cells. We describe novel mechanisms for Hsp60 reaching the extracellular environment that involve membrane-associated stages, as well as data on anti-Hsp60 antibodies found in human sera, both in normal subjects and patients affected by autoimmune diseases. Finally, we discuss possible therapeutic applications of anti-Hsp60 antibodies in cancer treatment, evaluating also side effects on non-tumor cells. In conclusion, the way for investigating Hsp60-targeted anti-tumor therapy is open, at least for those tumors that express Hsp60 on its surface and/or secrete it outside the cell, as is the search for the molecular mechanisms involved in Hsp60 translocation from cytosol to cell membrane: elucidation of this mechanism will greatly facilitate the optimization of chaperonotherapy centered on Hsp60 with anti-tumor efficacy and minimal side effects.

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Section: Anti-hsp60 Antibodies: Danger or Safety?supporting

confidence: 66%

Chaperonopathies and Chaperonotherapy. Hsp60 as Therapeutic Target in Cancer: Potential Benefits and Risks

Cappello

Angileri²,

Macario³

et al. 2013

Current Pharmaceutical Design

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“…By contrast, no Hsp60/p53 complex was present in our model. Further in vitro experiments are in progress to test this hypothesis, which, if confirmed, would provide a basis for using Hsp60 as a target for antitumoral therapy (Cappello et al, 2007;2008).…”

Section: Discussionmentioning

confidence: 93%

“…Hsp60, including probably the mitochondrial Cpn60, can be elevated in a number of human tumors (Czarnecka et al, 2006;Cappello et al, 2007;2008) and in the extracellular milieu, which can cause activation of an antitumor immune response (Calderwood et al, 2007). Whether and when mitochondrial and cytosolic Hsp60 have pro-or anti-apoptotic roles is still unclear, since there is evidence supporting both possibilities (Samali et al, 1999;Xanthoudakis et al, 1999;Gupta et al, 2005;Veereshwarayya et al, 2006;Chandra et al, 2007).…”

confidence: 99%

Upon oxidative stress, the antiapoptotic Hsp60/procaspase-3 complex persists in mucoepidermoid carcinoma cells

Campanella¹,

Bucchieri²,

Ardizzone³

et al. 2009

Eur J Histochem

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Hsp60, a mitochondrial chaperonin highly conserved during evolution, has been found elevated in the cytosol of cancer cells, both in vivo and in vitro, but its role in determining apoptosis during oxidative stress (OS) has not yet been fully elucidated. The aim of the present work was to study the effects of OS on Hsp60 levels and its interactions with procaspase- 3 (p-C3) and p53 in tumor cells. NCI-H292 (mucoepidermoid carcinoma) cells were exposed to various concentrations of hydrogen peroxide (H2O2) for 24 hours. Cell viability was determined by Trypan blue and MTT assays. DNA damage was assessed by the Comet assay, and apoptosis was measured by the AnnexinV cytofluorimetric test. Exposure to increasing concentrations of H2O2 resulted in a reduction of cell viability, DNA damage, and early apoptotic phenomena. Hsp60, p-C3, p53, and p21 were assessed by Western blotting and immunocytochemistry before and after OS. Hsp60 and p-C3 were present before and after OS induction. Immunoprecipitation experiments showed an Hsp60/p-C3 complex before OS that persisted after it, while an Hsp60/p53 complex was not detected in either condition. The presence of wild type (wt) p53 was confirmed by RT-PCR, and p21 detection suggested p53 activation after OS. We postulate that, although OS may induce early apoptosis in NCI-H292 cells, Hsp60 exerts an anti-apoptotic effect in these cells and, by extension, it may do so in other cancer cells

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“…Furthermore, it has been reported that mHsp60 has proapoptotic and antiapoptotic roles, depending on its cellular localization (18,19). Finally, mHsp60 and mHsp10 were found to change their expression pattern in tumor cells (20,21 …”

mentioning

confidence: 97%

The MitCHAP-60 Disease Is Due to Entropic Destabilization of the Human Mitochondrial Hsp60 Oligomer

Parnas

Nadler

Nisemblat

et al. 2009

Journal of Biological Chemistry

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The 60-kDa heat shock protein (mHsp60) is a vital cellular complex that mediates the folding of many of the mitochondrial proteins. Its function is executed in cooperation with the cochaperonin, mHsp10, and requires ATP. Recently, the discovery of a new mHsp60-associated neurodegenerative disorder, Mit-CHAP-60 disease, has been reported. The disease is caused by a point mutation at position 3 (D3G) of the mature mitochondrial Hsp60 protein, which renders it unable to complement the deletion of the homologous bacterial protein in Escherichia coli (Magen, D., Georgopoulos, C., Bross, P., Ang, D., Segev, Y., Goldsher, D., Nemirovski, A., Shahar, E., Ravid, S., Luder, A., Heno, B., Gershoni-Baruch, R., Skorecki, K., and Mandel, H. (2008) Am. J. Hum. Genet. 83, 30 -42). The molecular basis of the MitCHAP-60 disease is still unknown. In this study, we present an in vitro structural and functional analysis of the purified wild-type human mHsp60 and the MitCHAP-60 mutant. We show that the D3G mutation leads to destabilization of the mHsp60 oligomer and causes its disassembly at low protein concentrations. We also show that the mutant protein has impaired protein folding and ATPase activities. An additional mutant that lacks the first three amino acids (N-del), including Asp-3, is similarly impaired in refolding activity. Surprisingly, however, this mutant exhibits profound stabilization of its oligomeric structure. These results suggest that the D3G mutation leads to entropic destabilization of the mHsp60 oligomer, which severely impairs its chaperone function, thereby causing the disease.Type I chaperonins are essential molecular chaperones of the Hsp60 family found in eubacteria, mitochondria, and chloroplasts (1). They are key players in mediating the correct folding of newly translated, translocated, and stress-denatured proteins. The folding function of chaperonins is executed by the coordinated action of two oligomeric proteins, Hsp60 (also named cpn60 and in bacteria GroEL) and its co-chaperonin Hsp10 (also named cpn10 and in bacteria GroES). The GroEL molecule is composed of 14 subunits that form a barrel-like structure that consists of two back-to-back stacked heptameric rings with a large cavity at each end termed the "Anfinsen cage." GroES is a heptameric ring formed by ϳ10-kDa subunits. The co-chaperonin binds to the chaperonin in the presence of ATP and Mg 2ϩ via a short, unstructured, but highly conserved region known as the mobile loop (2, 3). Due to the stability of the GroEL/ES oligomers and the ease with which they can be purified from bacteria, they have become the primary targets for study in the field of chaperonins. As a result, almost all of our knowledge concerning the structure and mechanism of chaperonins, both Hsp60 and Hsp10, is based largely on data from experiments on these E. coli proteins. The chaperonin reaction cycle starts when a non-folded protein substrate binds to the surface of the cavity of one of the GroEL rings. ATP-dependent GroES binding to that (cis) ring causes a dramatic co...

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Hsp60 and Hsp10 as antitumour molecular agents

Cited by 34 publications

References 26 publications

Chaperonopathies and Chaperonotherapy. Hsp60 as Therapeutic Target in Cancer: Potential Benefits and Risks

Chaperonopathies and Chaperonotherapy. Hsp60 as Therapeutic Target in Cancer: Potential Benefits and Risks

Upon oxidative stress, the antiapoptotic Hsp60/procaspase-3 complex persists in mucoepidermoid carcinoma cells

The MitCHAP-60 Disease Is Due to Entropic Destabilization of the Human Mitochondrial Hsp60 Oligomer

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