Hsps are up-regulated in melanoma tissue and correlate with patient clinical parameters

Shipp, Christopher; Weide, Benjamin; Derhovanessian, Evelyna; Pawelec, Graham

doi:10.1007/s12192-012-0363-1

Cited by 21 publications

(12 citation statements)

References 35 publications

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“…While HSP90 level is low in benign melanocytic nevi, it increases during melanoma progression [36]. Consequently, a high level of HSP90 was assessed in more than 50% of melanoma tumors [37,38]. Although high HSP90 expression is not a predictive factor for patient survival, HSP90 level significantly correlated with the Clark level and increased Breslow depth in primary melanomas [36].…”

Section: Hsp90 In Melanomamentioning

confidence: 99%

Inhibitors of HSP90 in melanoma

Mielczarek-Lewandowska

Hartman

Czyż

2019

Apoptosis

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HSP90 (heat shock protein 90) is an ATP-dependent molecular chaperone involved in a proper folding and maturation of hundreds of proteins. HSP90 is abundantly expressed in cancer, including melanoma. HSP90 client proteins are the key oncoproteins of several signaling pathways controlling melanoma development, progression and response to therapy. A number of natural and synthetic compounds of different chemical structures and binding sites within HSP90 have been identified as selective HSP90 inhibitors. The majority of HSP90-targeting agents affect N-terminal ATPase activity of HSP90. In contrast to N-terminal inhibitors, agents interacting with the middle and C-terminal domains of HSP90 do not induce HSP70dependent cytoprotective response. Several inhibitors of HSP90 were tested against melanoma in pre-clinical studies and clinical trials, providing evidence that these agents can be considered either as single or complementary therapeutic strategy. This review summarizes current knowledge on the role of HSP90 protein in cancer with focus on melanoma, and provides an overview of structurally different HSP90 inhibitors that are considered as potential therapeutics for melanoma treatment.

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Section: Hsp90 In Melanomamentioning

confidence: 99%

Inhibitors of HSP90 in melanoma

Mielczarek-Lewandowska

Hartman

Czyż

2019

Apoptosis

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“…Moreover, the relevant role that chaperones (for example; HSP70, HSP90) play in preserving melanoma survival and plasticity is emphasized by their correlation with disease progression (103, 104) and the manifested vulnerability that melanoma cells exhibit following perturbations of global proteostasis. A study comparing the expression levels of HSPs across patient clinical parameters showed that, with the notable exception of HSP32, whose expression correlated with improved patient survival, increased expression of HSP90 and HSP40 correlated with advanced stages of melanoma, and in the case of HSP40 with decreased patient survival (105). In line with this, another study observed an indispensable role of HSF1 in melanoma progression and migration, thus highlighting its potential as therapeutic target in melanoma (106).…”

Section: Adapt and Survive: Alteration Of Cytoplasmic And Upr-based Pmentioning

confidence: 99%

Adapt, Recycle, and Move on: Proteostasis and Trafficking Mechanisms in Melanoma

et al. 2016

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Melanoma has emerged as a paradigm of a highly aggressive and plastic cancer, capable to co-opt the tumor stroma in order to adapt to the hostile microenvironment, suppress immunosurveillance mechanisms, and disseminate. In particular, oncogene- and aneuploidy-driven dysregulations of proteostasis in melanoma cells impose a rewiring of central proteostatic processes, such as the heat shock and unfolded protein responses, autophagy, and the endo-lysosomal system, to avoid proteotoxicity. Research over the past decade has indicated that alterations in key nodes of these proteostasis pathways act in conjunction with crucial oncogenic drivers to increase intrinsic adaptations of melanoma cells against proteotoxic stress, modulate the high metabolic demand of these cancer cells and the interface with other stromal cells, through the heightened release of soluble factors or exosomes. Here, we overview and discuss how key proteostasis pathways and vesicular trafficking mechanisms are turned into vital conduits of melanoma progression, by supporting cancer cell’s adaptation to the microenvironment, limiting or modulating the ability to respond to therapy and fueling melanoma dissemination.

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“…By inhibiting Hsp90, 17-AAG causes the destabilization of the products of several mutant oncogenes, including BRAF, CRAF and NRAS [17] . Through its role in regulating the conformation, stability and function of several key oncogenic client proteins, Hsp90 is essential in maintaining malignant transformation and in increasing the survival, growth, and invasive potential of cancer cells, including melanomas [18] [19] . Several members of this drug class have been tested in human clinical trials [20] , and while the drugs may slow tumor growth, to date none have succeeded as single agents [21] .…”

Section: Introductionmentioning

confidence: 99%

Heat Shock Protein-90 Inhibitors Enhance Antigen Expression on Melanomas and Increase T Cell Recognition of Tumor Cells

et al. 2014

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In an effort to enhance antigen-specific T cell recognition of cancer cells, we have examined numerous modulators of antigen-expression. In this report we demonstrate that twelve different Hsp90 inhibitors (iHsp90) share the ability to increase the expression of differentiation antigens and MHC Class I antigens. These iHsp90 are active in several molecular and cellular assays on a series of tumor cell lines, including eleven human melanomas, a murine B16 melanoma, and two human glioma-derived cell lines. Intra-cytoplasmic antibody staining showed that all of the tested iHsp90 increased expression of the melanocyte differentiation antigens Melan-A/MART-1, gp100, and TRP-2, as well as MHC Class I. The gliomas showed enhanced gp100 and MHC staining. Quantitative analysis of mRNA levels showed a parallel increase in message transcription, and a reporter assay shows induction of promoter activity for Melan-A/MART-1 gene. In addition, iHsp90 increased recognition of tumor cells by T cells specific for Melan-A/MART-1. In contrast to direct Hsp90 client proteins, the increased levels of full-length differentiation antigens that result from iHsp90 treatment are most likely the result of transcriptional activation of their encoding genes. In combination, these results suggest that iHsp90 improve recognition of tumor cells by T cells specific for a melanoma-associated antigen as a result of increasing the expressed intracellular antigen pool available for processing and presentation by MHC Class I, along with increased levels of MHC Class I itself. As these Hsp90 inhibitors do not interfere with T cell function, they could have potential for use in immunotherapy of cancer.

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Hsps are up-regulated in melanoma tissue and correlate with patient clinical parameters

Cited by 21 publications

References 35 publications

Inhibitors of HSP90 in melanoma

Inhibitors of HSP90 in melanoma

Adapt, Recycle, and Move on: Proteostasis and Trafficking Mechanisms in Melanoma

Heat Shock Protein-90 Inhibitors Enhance Antigen Expression on Melanomas and Increase T Cell Recognition of Tumor Cells

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