AntiTumor Response and Heat Shock Proteins (HSP): A friend or Foe relationship (original) (raw)
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Oncotarget, 2014
Hsp70 chaperone is known to stimulate anti-tumour immunity in a variety of cancer models. Here we demonstrated that the addition of purified recombinant Hsp70 to the culture medium facilitated cancer cell cytolysis by lymphocytes. Importantly, exogenous Hsp70 triggered secretion of the intracellular Hsp70 to a cell surface and extracellular milieu, which played a role in cytolysis because down-regulation of the endogenous Hsp70 reduced both its presence at the cell surface and the lymphocyte-mediated cytolysis. Inhibitors that target both the ATPase and the peptide-binding domains of Hsp70 molecule potently decreased its anti-tumor effect. Using a variety of cell transport markers and inhibitors, we showed that the exchange of exogenous and intracellular Hsp70 is supported by classical and non-classical transport pathways, with a particular role of lipid rafts in the chaperone's intracellular transport. In conclusion, exogenous Hsp70 can eject endogenous Hsp70, thus exerting ant...
Heat Shock Protein 70 Is Required for the Survival of Cancer Cells
Annals of the New York Academy of Sciences, 2006
The major stress-inducible heat shock protein, Hsp70, is a chaperone protein abundantly and preferentially expressed in human tumors and tumor cell lines. Owing to the ability of Hsp70 to protect cells from a wide range of apoptotic and necrotic stimuli, it has been assumed that Hsp70 may confer survival advantage to tumor cells. To investigate this hypothesis in human tumor cell lines, we generated an adenovirus expressing antisense Hsp70 (Ad.asHsp70). The effective and specific depletion of Hsp70 by Ad.asHsp70 resulted in massive cell death of all tumorigenic cell lines tested (carcinomas of breast, colon, prostate and liver as well as glioblastoma). In spite of an effective depletion of Hsp70, Ad.asHsp70 had no effect on the survival or growth of fetal fibroblasts or non-tumorigenic epithelial cells of breast or prostate. Anti-apoptotic proteins Bcl-2, Bcl-XL and CrmA as well as peptide-inhibitors of caspases, DEVD-CHO and zVAD-FMK, failed to rescue tumor cells from Ad.asHsp70-induced cell death. These results indicate that the high expression of Hsp70 is a prerequisite for the survival of human cancer cells of various origins and reveal Hsp70 as the only protein described so far whose expression is specifically needed for the survival of tumorigenic cells.
The Role of Heat Shock Proteins in Cancer
The Role of Heat Shock Proteins in Cancer, 2019
Heat shock proteins (HSPs) are a group of ubiquitous intracellular molecules that HSP27, HSP70 and HSP90 are powerful chaperones. HSPs function as molecular chaperones in numerous processes, such as protein folding and transport, and are induced under stress conditions, such as fever and radiation. Certain HSPs are potent inducers of innate and antigenspecific immunity. They activate natural killer cells, increase presentation of antigens to effector cells and augment T-cell and humoral immune responses against their associated antigens. HSPs are often over expressed in cancer cells and this constitutive expression is necessary for cancer cells' survival. Their roles in priming multiple host defense pathways are being exploited in vaccine development for cancer and infectious diseases. HSP-targeting drugs have therefore emerged as potential anti-cancer agents.
Heat Shock Proteins: Conditional Mediators of Inflammation in Tumor Immunity
Frontiers in Immunology, 2012
Heat shock protein (HSP)-based anticancer vaccines have undergone successful preclinical testing and are now entering clinical trial. Questions still remain, however regarding the immunological properties of HSPs. It is now accepted that many of the HSPs participate in tumor immunity, at least in part by chaperoning tumor antigenic peptides, introducing them into antigen presenting cells such as dendritic cells (DC) that display the antigens on MHC class I molecules on the cell surface and stimulate cytotoxic lymphocytes (CTL). However, in order for activated CD8+ T cells to function as effective CTL and kill tumor cells, additional signals must be induced to obtain a sturdy CTL response. These include the expression of co-stimulatory molecules on the DC surface and inflammatory events that can induce immunogenic cytokine cascades.That such events occur is indicated by the ability of Hsp70 vaccines to induce antitumor immunity and overcome tolerance to tumor antigens such as mucin1. Secondary activation of CTL can be induced by inflammatory signaling through Toll-like receptors and/or by interaction of antigen-activated T helper cells with the APC. We will discuss the role of the inflammatory properties of HSPs in tumor immunity and the potential role of HSPs in activating T helper cells and DC licensing.
Heat shock proteins as novel therapeutic targets in cancer
In vivo (Athens, Greece)
Heat shock proteins (HSPs) are evolutionarily conserved molecules synthesised by cells exposed to sub-lethal stresses. Acting as molecular chaperones, HSPs protect cells from environmental stress damage by assisting in proper folding and stabilisation of proteins. In addition, they help to sequester severely damaged proteins for degradation. Owing to the nature of their function, HSPs are often found to be overexpressed in a wide range of cancers. Members of the HSP family have been implicated in cancer growth as promoting tumour cell proliferation as well as inhibiting cellular death pathways. In recent years, several HSP90 client proteins have been validated as clinically important therapeutic targets for treatment of cancer, and inhibitors of HSP90 have emerged as potentially beneficial anticancer agents. This review explores the involvement of HSPs in cancer and the development of several anticancer agents with promising therapeutic applications.
Annals of the New York Academy of Sciences, 2007
Heat shock proteins (Hsps) are highly conserved and inhabit nearly all subcellular locations where they perform a variety of chaperoning functions including folding and unfolding of nascent polypeptides, proteins, transport of proteins, and support of antigen presentation processes. Apart from their intracellular location Hsps with a molecular weight of 70 kDa (Hsp70) also have been found on the plasma membrane of malignantly transformed cells, on virally/bacterial infected cells and in the extracellular space. Depending on their intra-and extracellular location Hsps exert either protection against environmental stress or act as potent stimulators of the immune response. In this review we address the dual function of intracellular and extracellular located small Hsps and members of the Hsp70 family and its immunological consequences for cancer immunity.
Heat shock proteins in oncology: Diagnostic biomarkers or therapeutic targets
Biochimica Et Biophysica Acta-reviews on Cancer, 2011
Heat shock proteins (HSP) are a family of proteins induced in cells exposed to different insults. This induction of HSPs allows cells to survive stress conditions. Mammalian HSPs have been classified into six families according to their molecular size: HSP100, HSP90, HSP70, HSP60, HSP40 and small HSPs (15 to 30 kDa) including HSP27. These proteins act as molecular chaperones either helping in the refolding of misfolded proteins or assisting in their elimination if they become irreversibly damaged. In recent years, proteomic studies have characterized several different HSPs in various tumor types which may be putative clinical biomarkers or molecular targets for cancer therapy. This has led to the development of a series of molecules capable of inhibiting HSPs. Numerous studies speculated that over-expression of HSP is in part responsible for resistance to many anti-tumor agents and chemotherapeutics. Hence, from a pharmacological point of view, the co-administration of HSP inhibitors together with other anti-tumor agents is of major importance in overcoming therapeutic resistance. In this review, we provide an overview of the current status of HSPs in autoimmune, cardiovascular, and neurodegenerative diseases with special emphasis on cancer.
Heat shock proteins HSP70 and GP96: structural insights
Cancer Immunology, Immunotherapy, 2006
Several heat shock proteins (HSPs) act as potent adjuvants for eliciting anti-tumor immunity. HSP-based tumor vaccine strategies have been highly successful in animal models and are undergoing testing in clinical trials. It is generally accepted that HSPs, functioning as chaperones for tumor antigens, elicit tumor-specific adaptive immune responses. HSPs also appear to induce innate immune responses in an antigen-independent fashion.
Heat shock proteins, autoimmunity, and cancer treatment
Autoimmune diseases, 2012
Heat shock proteins (HSPs) have been linked to the therapy of both cancer and inflammatory diseases, approaches that utilize contrasting immune properties of these proteins. It would appear that HSP family members Hsp60 and Hsp70, whether from external sources or induced locally during inflammation, can be processed by antigen-presenting cells and that HSP-derived epitopes then activate regulatory T cells and suppress inflammatory diseases. These effects also extend to the HSP-rich environments of cancer cells where elevated HSP concentrations may participate in the immunosuppressive tumor milieu. However, HSPs can also be important mediators of tumor immunity. Due to their molecular chaperone properties, some HSPs can bind tumor-specific peptides and deliver them deep into the antigen-processing pathways of antigen-presenting cells (APCs). In this context, HSP-based vaccines can activate tumor-specific immunity, trigger the proliferation and CTL capabilities of cancer-specific CD8+...