Chaperonin Hsp60 and Cancer Therapies

Abstract

The heat shock protein 60 (Hsp60) is a chaperonin belonging to the chaperoning (chaperone) system that typically contributes to protein homeostasis inside mitochondria, but also plays various non-canonical roles unrelated to protein quality control beyond the organelle. Chaperonopathies are disorders in which chaperones play an etiologic-pathogenic role and contribute to the onset/progression of disease. Hsp60 chaperonopathies by mistake are diseases in which the chaperonin is apparently normal (as far as it can be determined with current methodologies) but it actively contributes to pathology, for example in certain types of cancer, and autoimmune and chronic inflammatory disorders. In certain cancers, Hsp60 is associated with the onset of malignancy and metastasization, although the mechanisms are poorly understood. In this chapter, we summarize findings on Hsp60 quantitative changes and distribution alterations in cells and tissues accompanying tumor initiation and progression. We also discuss the potential of HSP60-based anticancer therapies that are currently being investigated.Methods Journals and data bases were surveyed, and pertinent works were chosen for discussion. Results The data have stimulated experimental and clinical studies aiming at establishing the usefulness of Hsp60 as biomarker for diagnosis, and for assessing prognosis and response to treatment. Likewise, investigations are ongoing on the possible use of Hsp60 as a therapeutic agent or target. The reported results indicate that in neoplasms, Hsp60 migrates outside its canonical location, the mitochondrion, augments in the cytoplasm and plasma-cell membrane, and exits the cell via lipid rafts-exosomes. Exosomal Hsp60 occurs in extracellular fluids such as blood, through which it reaches target cells near and far, normal or cancerous. With these target cells, exosomes carrying Hsp60 and other molecules interact and, thereby, modify their functions. Thus, detection of exosomal Hsp60 in body fluids appears as a promising variety of liquid biopsy applicable to monitoring cancers already diagnosed and to screen for malignancies before they are clinically manifest. We also discuss Hsp60-based vaccines as a novel means of eliminating cancer cells with cytotoxic T lymphocytes (CTL). Tumor-derived Hsp60 associated with a tumorderived antigen activates CD8+ T cells and induces an antitumor immune response. It is highly probable that soon there will be implementation of clinical trials, involving the use of Hsp60 alone or in various combinations and complexes to prevent cancer progression and treat patients. Conclusions Hsp60 is actively involved in tumor development and progression. Its presence in extracellular fluids renders it a potential non-invasive biomarker. Also, considering the antitumor activities of Hsp60 observed in some types of cancer one can foresee a bright future for Hsp60-based therapies.