Toward Developing Chemical Modulators of Hsp60 as Potential Therapeutics

Abstract

The 60 kDa heat shock protein (Hsp60) is classically known as a mitochondrial chaperonin protein working together with co-chaperonin 10 kDa heat shock protein (Hsp10). This chaperonin complex is essential for folding proteins newly imported into mitochondria. However, Hsp60, and/or Hsp10 have also been shown to reside in other subcellular compartments including extracellular space, cytosol, and nucleus. The proteins in these extra-mitochondrial compartments may possess a wide range of functions dependent or independent of its chaperoning activity. But the mechanistic details remain unknown. Mutations in Hsp60 gene have been shown to be associated with neurodegenerative disorders. Abnormality in expression level and/or subcellular localization have also been detected from different diseased tissues including inflammatory diseases and various cancers. Therefore, there is a strong interest in developing small molecule modulators of Hsp60. Most of the reported inhibitors were discovered through various chemoproteomics strategies. In this review, we will describe the recent progress in this area with reported inhibitors from both natural products and synthetic compounds. The former includes mizoribine, epolactaene, myrtucommulone, stephacidin B, and avrainvillamide while the latter includes o-carboranylphenoxyacetanilides and gold (III) porphyrins. The potencies of the known inhibitors range from low micromolar to millimolar concentrations. The potential applications of these inhibitors include anti-cancer, anti-inflammatory diseases, and anti-autoimmune diseases.

Role of Mitochondrial Stress Protein HSP60 in Diabetes-Induced Neuroinflammation

“…Even though HSP60 is predominantly found in mitochondria, recent data suggest that it is also capable of being localized in the cytosol, nucleus, cell surface, intercellular vesicles, and extracellular environments (such as in blood circulation) [63]. HSP60 is secreted from cells into the extracellular environment through either endoplasmic reticulum and the Golgi apparatus or binding with exosomes and lipid channels [64].…”

Heat Shock Protein 60 in Hepatocellular Carcinoma: Insights and Perspectives

“…Recent reports highlight the perspectives of targeting HSP60 as a future tool for cancer treatment (Nakamura and Minegishi, 2013;Cappello et al, 2014;Meng et al, 2018). In fact, HSP60 inhibition has been implemented as a therapeutic strategy in various types of cancers including melanoma (Kamm et al, 2019), pancreatic cancer (Zhou et al, 2018), and ovarian cancer (Guo et al, 2019).…”

“…Compared with other HSPs such as HSP90 and HSP70, few compounds have been known to target HSP60 in the oncology field (Nakamura and Minegishi, 2013). Recent reports have shed the light on the potential HSP60 inhibitors and their usage for cancer therapeutic purposes (Meng et al, 2018). According to their mechanism of action, HSP60 inhibitors have been classified into type I inhibitors and type II inhibitors.…”

“…Type I inhibitors act by blocking the ATP binding site of HSP60 and subsequently interfering with ATP hydrolysis and folding activities, whereas Type II compounds function through covalent interaction with specific cysteine residues within the HSP60 molecule. Nevertheless, full understanding of the exact mechanisms of HSP60 inhibitors is still lacking (Meng et al, 2018). Table 2 provides an overview about the known HSP60 Despite its poorly understood mechanisms, it suppresses HSP60 and performs significant anticancer activities Lease et al, 2013;Teo et al, 2014;Hu et al, 2016 a Nakamura andMinegishi, 2013;Meng et al, 2018. inhibitors which might be used in future HCC studies or combination therapies for cancer treatment.…”

“…HSP plays numerous physiological roles but can also be pathogenic in various conditions, including cancer and neurodegenerative diseases (Cappello et al, 2008;Bross et al, 2012;Zhou et al, 2018). Recent reports highlight the role and implication of HSP60 in human cancer development and management whereby its targeting has revealed promising therapeutic outcomes (Pace et al, 2013;Li et al, 2014;Meng et al, 2018).…”