A modified HSP70 inhibitor shows broad activity as an anticancer agent (original) (raw)
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Targeting Hsp70: A possible therapy for cancer
Cancer letters, 2016
In all organisms, heat-shock proteins (HSPs) provide an ancient defense system. These proteins act as molecular chaperones by assisting proper folding and refolding of misfolded proteins and aid in the elimination of old and damaged cells. HSPs include Hsp100, Hsp90, Hsp70, Hsp40, and small HSPs. Through its substrate-binding domains, Hsp70 interacts with wide spectrum of molecules, ranging from unfolded to natively folded and aggregated proteins, and provides cytoprotective role against various cellular stresses. Under pathophysiological conditions, the high expression of Hsp70 allows cells to survive with lethal injuries. Increased Hsp70, by interacting at several points on apoptotic signaling pathways, leads to inhibition of apoptosis. Elevated expression of Hsp70 in cancer cells may be responsible for tumorigenesis and for tumor progression by providing resistance to chemotherapy. In contrast, inhibition or knockdown of Hsp70 reduces the size of tumors and can cause their comple...
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.
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 proteins as targets in oncology
Clinical & Translational Oncology, 2010
Heat shock proteins are ubiquitous molecular chaperones involved in posttranslational folding, stability, activation and maturation of many proteins that are essential mediators of signal transduction and cell cycle progression. Hsp90 proteins are the best studied proteins of this family. A growing number of Hsp90 client proteins have been shown to be important for the development, proliferation and survival of several types of cancer. Inhibition of Hsp90 leads to the degradation of known oncogene products, such as Her2, BRAF and others, leading to the simultaneous blockade of multiple oncogenic transduction pathways. Hsp90 inhibitors, derived from the natural compound geldanamycin, are attractive targets for anticancer drug development. We will review the clinical data on Hsp90 inhibitors in different malignancies. The best known of them, 17-AAG, has shown significant antitumour activity against a broad variety of cancers in preclinical studies, including breast, myeloma, melanoma, prostate and lung cancers. Hsp90 inhibitors can be used as single agents or in combination with other targeted treatments or chemotherapy and radiotherapy. The results of clinical phase II and III trials evaluating the efficacy of these drugs in different types of tumours are awaited.
Heat shock protein 70-2 (HSP70-2) overexpression in breast cancer
Journal of Experimental & Clinical Cancer Research, 2016
Background: Breast cancer is one of the leading cause of cancer-related deaths in women worldwide and increasing rapidly in developing countries. In the present study, we investigated the potential role and association of HSP70-2 with breast cancer. Methods: HSP70-2 expression was examined in 154 tumor and 103 adjacent non-cancerous tissue (ANCT) specimens and breast cancer cell lines (MCF7, BT-474, SK-BR-3 and MDA-MB-231) by RT-PCR, quantitative-PCR, immunohistochemistry, Western blotting, flow cytometry and indirect immunofluorescence. Plasmid driven short hairpin RNA approach was employed to validate the role of HSP70-2 in cellular proliferation, senescence, migration, invasion and tumor growth. Further, we studied the effect of HSP70-2 protein ablation on signaling cascades involved in apoptosis, cell cycle and Epithelial-Mesenchymal-Transition both in culture as well as in-vivo human breast xenograft mouse model. Results: HSP70-2 expression was detected in majority of breast cancer patients (83 %) irrespective of various histotypes, stages and grades. HSP70-2 expression was also observed in all breast cancer cells (BT-474, MCF7, MDA-MB-231 and SK-BR-3) used in this study. Depletion of HSP70-2 in MDA-MB-231 and MCF7 cells resulted in a significant reduction in cellular growth, motility, onset of apoptosis, senescence, cell cycle arrest as well as reduction of tumor growth in the xenograft model. At molecular level, down-regulation of HSP70-2 resulted in reduced expression of cyclins, cyclin dependent kinases, anti-apoptotic molecules and mesenchymal markers and enhanced expression of CDK inhibitors, caspases, pro-apoptotic molecules and epithelial markers. Conclusions: HSP70-2 is over expressed in breast cancer patients and was involved in malignant properties of breast cancer. This suggests HSP70-2 may be potential candidate molecule for development of better breast cancer treatment.
Hsp70 in cancer: A double agent in the battle between survival and death
Journal of Cellular Physiology, 2020
The heat shock protein (Hsps) superfamily, also known as molecular chaperones, are highly conserved and present in all living organisms and play vital roles in protein fate. The HspA1A (Hsp70‐1), called Hsp70 in this review, is expressed at low or undetectable levels in most unstressed normal cells, but numerous studies have shown that diverse types of tumor cells express Hsp70 at the plasma membrane that leads to resistance to programmed cell death and tumor progression. Hsp70 is released into the extracellular milieu in three forms including free soluble, complexed with cancer antigenic peptides, and exosome forms. Therefore, it seems to be a promising therapeutic target in human malignancies. However, a great number of studies have indicated that both intracellular and extracellular Hsp70 have a dual function. A line of evidence presented that intracellular Hsp70 has a cytoprotective function via suppression of apoptosis and lysosomal cell death (LCD) as well as that extracellula...
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.
AntiTumor Response and Heat Shock Proteins (HSP): A friend or Foe relationship
Heat shock proteins (HSP), particularly inducible HSP72 have a role in generating an effective antitumoral response as immunogenic peptide carriers or as immunostimulants; inducing activation and maturation of dendritic cells (DC). Their basic function is as molecular chaperones, ATP dependant; increasing cell survival under any type of stress. Chaperone function is natural to protein family HSP70 structure, having a C-terminal domain that binds unfolded proteins and peptides and a N-terminal ATPase domain that controls peptide binding pocket opening and closing. Their immunostimulant role might antagonized with their protective activity against cell death induced by stress or cytotoxic agents. Inducible HSP70 is implicated in carrying out these two functions; purpose of the present review. Furthermore, is possible other members of HSP70 protein family to be implicated, but in different ways; by inducing immune response or as tumoral growth promoters inhibiting apoptosis. Comprehension of mechanisms that regulate both activities, is crucial in developing an effective antitumoral therapy through the search of substances that preserving their immunogenic potential do not increase tumor resistance to classical antitumoral therapy