The Role of HSP70 in Cancer and its Exploitation as a Therapeutic Target.

Abstract

Sustained proliferation and genetic instability of cancer cells are associated with enhanced production of mutated and conformationally unstable proteins. Excessive proteosynthesis along with increased metabolic turnover generates stress conditions that cancer cells must permanently compensate for. Tumor cells thus become dependent on the maintenance of protein homeostasis, which involves protein quality control, folding, transport and stabilization. These tasks are provided by molecular chaperones, predominantly the stress proteins HSP70 and HSP90. Their expression and activity is increased in all malignant tumors, where they associate with their cochaperones to form large multiprotein complexes. HSP70 and HSP90 maintain the malignant phenotype because they facilitate the folding of numerous oncogenic proteins, maintain proliferative potential, and inhibit apoptosis. In this regard, heat-shock proteins represent an important target for cancer therapy because their inactivation results in the simultaneous blockade of multiple signaling pathways. Although several specific HSP90 inhibitors have been developed in the past decade, their antitumor activity as single agents is limited due to the induction of HSP70, which enables cell survival. Inhibitors of HSP70 thus present new possibilities for targeting proteostatic mechanisms in cancer cells. The aim of this article is to summarize information on the structure of HSP70 and its role in maintaining protein homeostasis in normal and cancer cells. The mechanisms of HSP70 inhibition by low-molecular weight compounds and their application in targeted antitumor therapy are also described. Key words: HSP70 - stress proteins - molecular chaperons - cellular stress - tumours - protein folding This work was supported by the project MEYS - NPS I - LO1413. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Accepted: 16. 08. 2018.