Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells

Abstract

The fundamental challenge in fighting cancer is the development of protective agents able to interfere with the classical pathways of malignant transformation, such as extracellular matrix remodeling, epithelial–mesenchymal transition and, alteration of protein homeostasis. In the tumors of the brain, proteotoxic stress represents one of the main triggering agents for cell transformation. Curcumin is a natural compound with anti-inflammatory and anti-cancer properties with promising potential for the development of therapeutic drugs for the treatment of cancer as well as neurodegenerative diseases. Among the mediators of cancer development, HSP60 is a key factor for the maintenance of protein homeostasis and cell survival. High HSP60 levels were correlated, in particular, with cancer development and progression, and for this reason, we investigated the ability of curcumin to affect HSP60 expression, localization, and post-translational modifications using a neuroblastoma cell line. We have also looked at the ability of curcumin to interfere with the HSP60/HSP10 folding machinery. The cells were treated with 6, 12.5, and 25 µM of curcumin for 24 h, and the flow cytometry analysis showed that the compound induced apoptosis in a dose-dependent manner with a higher percentage of apoptotic cells at 25 µM. This dose of curcumin-induced a decrease in HSP60 protein levels and an upregulation of HSP60 mRNA expression. Moreover, 25 µM of curcumin reduced HSP60 ubiquitination and nitration, and the chaperonin levels were higher in the culture media compared with the untreated cells. Furthermore, curcumin at the same dose was able to favor HSP60 folding activity. The reduction of HSP60 levels, together with the increase in its folding activity and the secretion in the media led to the supposition that curcumin might interfere with cancer progression with a protective mechanism involving the chaperonin.

Modulating disease-relevant tau oligomeric strains by small molecules

“…Curcumin is a plant-derived polyphenol that has been proposed as a promising candidate for the development of preventive and therapeutic approaches for many diseases, including neurodegenerative disorders ( 36 – 40 ). However, curcumin therapeutic application for AD and other neurodegenerative diseases is challenging due to its poor water solubility and low oral bioavailability ( 41 , 42 ).…”

The Challenging Riddle about the Janus-Type Role of Hsp60 and Related Extracellular Vesicles and miRNAs in Carcinogenesis and the Promises of Its Solution

“…Some possibilities are to (i) identify compounds and/or methods that will induce a antitumor immune response by promoting the presence of Hsp60 on the surface of tumor-cells [172]; (ii) develop Hsp60 vaccines exploiting its potential for inducing the production of cytokines by interaction with monocytes and macrophages, and by manipulating its ability to bind and activate TLR-2 in CD4+CD25+ regulatory T cells and TLR-4 in B cells [173]; and (iii) identify compounds able to modulate Hsp60 expression, in order to reduce or enhance its activity in those tumors in which it displays a pro-or anti-tumorigenic role, respectively. Understanding the mode of action of Hsp60 and its regulation by miRNAs in different tissue and tumor types will help in the development of novel therapeutic strategies for cancer therapy [68,112,174]. Moreover, the utilization of advanced drug delivery systems, as exosome-like vesicles promise to be, to deliver molecules, such as miRNAs known to regulate Hsp60, and internalize them in the target cells, should be actively investigated to standardize the particles and their contents as well as their isolation from cancer patients.…”

“…It puts Hsp60 in the stage's center and presents it as a target for developing treatment strategies aimed at inhibiting-blocking this collaborator with the enemy from the inside. For example, Hsp60 downregulation by chemical compounds suppressed cancer-cell proliferation and tumor progression and enhanced the beneficial effects of anti-cancer treatments [62,69,90,[108][109][110][111][112]. It was observed that Hsp60 knockdown inhibited tumor progression by altering mitochondrial homeostasis and inactivating the mTOR pathway, in ovarian cancer and glioblastoma [90,109].…”

Mutual Two-Way Interactions of Curcumin and Gut Microbiota

“…This issue needs to be clarified in future research. Considering the pleotropic effect of curcumin on neurodegenerative diseases, cancers and immune disorders, curcumin is a promising substance for treating disease today without causal treatment [1,2,10,[51][52][53][54][55][56][57]. In addition, it is a safe, inexpensive substance, easily accessible and penetrates the blood-brain barrier and neuronal membranes, which is its great advantage [1][2][3]7].…”