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      The Multiple Roles and Therapeutic Potential of Molecular Chaperones in Prostate Cancer

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          Abstract

          Prostate cancer (PCa) is one of the most common cancer types in men worldwide. Heat shock proteins (HSPs) are molecular chaperones that are widely implicated in the pathogenesis, diagnosis, prognosis, and treatment of many cancers. The role of HSPs in PCa is complex and their expression has been linked to the progression and aggressiveness of the tumor. Prominent chaperones, including HSP90 and HSP70, are involved in the folding and trafficking of critical cancer-related proteins. Other members of HSPs, including HSP27 and HSP60, have been considered as promising biomarkers, similar to prostate-specific membrane antigen (PSMA), for PCa screening in order to evaluate and monitor the progression or recurrence of the disease. Moreover, expression level of chaperones like clusterin has been shown to correlate directly with the prostate tumor grade. Hence, targeting HSPs in PCa has been suggested as a promising strategy for cancer therapy. In the current review, we discuss the functions as well as the role of HSPs in PCa progression and further evaluate the approach of inhibiting HSPs as a cancer treatment strategy.

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          Most cited references231

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          Molecular chaperones in protein folding and proteostasis.

          Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.
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            Hsp70 chaperones: Cellular functions and molecular mechanism

            Abstract. Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.
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              The HSP90 chaperone machinery

              The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis. Recent progress has shed light on the interactions of HSP90 with its clients and co-chaperones, and on their functional implications. This opens up new avenues for the development of drugs that target HSP90, which could be valuable for the treatment of cancers and protein-misfolding diseases.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                16 August 2019
                August 2019
                : 11
                : 8
                : 1194
                Affiliations
                [1 ]Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, Cairo University, 12211 Giza, Egypt
                [2 ]Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
                [3 ]School of Arts and Sciences, Lebanese American University, Beirut 1102 2801, Lebanon
                Author notes
                [* ]Correspondence: hassan.naim@ 123456tiho-hannover.de ; Tel.: +49-511-953-8780; Fax: +49-511-953-8585
                Author information
                https://orcid.org/0000-0002-4405-5703
                https://orcid.org/0000-0003-4884-8425
                Article
                cancers-11-01194
                10.3390/cancers11081194
                6721600
                31426412
                487b72ba-a5a5-4148-850c-8586c01a11d8
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 17 July 2019
                : 15 August 2019
                Categories
                Review

                prostate cancer,therapeutic resistance,heat shock proteins (hsps),molecular chaperones,hsps inhibitors,biomarkers

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