Review articleMelatonin as a proteasome inhibitor. Is there any clinical evidence?
Graphical abstract
Introduction
Some of the major proteins of significance in cancer susceptibility include the tumor suppressor factor, p53, cell cycle regulator, p27, transcription factor NF-κB, anti-apoptotic factor Bcl-2, and the pro-apoptotic factor Bax. Cellular levels of these proteins are controlled by the ubiquitin–proteasome system and are targets of the proteasome inhibitor, bortezomib (Chen et al., 2011, Fuchs, 2013). Each of these proteins has also been reported to be influenced by the naturally-occurring indole, melatonin (Fig. 1). The increasing number of proteins reported as regulated by both the proteasome and by melatonin suggests the hypothesis that melatonin acts as an inhibitor of a component of the ubiquitin–proteasome system (Vriend and Reiter, 2014). Herein, we review the signal transduction proteins whose levels are modulated both by the ubiquitin–proteasome system and by melatonin, and we discuss mechanisms by which melatonin could interact with the ubiquitin–proteasome system in cancer cells. The use of proteasome inhibitors in treating some hematological disorders and cancers raises the question of whether melatonin should be added to drug regimens used to treat specific malignancies that are sensitive to proteasome inhibitors.
Section snippets
Shared targets for proteasome inhibitors and melatonin
Several major targets of proteasome inhibitors were identified followed by the approval of bortezomib by the US Food and Drug Administration in 2004 for treatment of multiple myeloma. The effects of proteasome inhibitors on signal transduction proteins have been regularly reviewed (e.g. Adams et al., 1999, Chen et al., 2011, Crawford et al., 2011, Kisselev et al., 2013, Wu and Shi, 2013). Thus, treatment with proteasome inhibitors increases tumor suppressor protein p53, increases the cell cycle
NF-κB
NF-κB as a transcription factor stimulates the expression of a number of genes related to oxidative stress, the immune response, cytokine production and apoptosis (Crawford et al., 2011). It is regulated in a complex manner by the ubiquitin–proteasome system. Degradation of the NF-κB inhibitor, IκK, by the proteasome results in activation of NF-κB (Traenchner et al., 1994, Chen, 2005, Gilmore, 2006, Brasier, 2006, Perkins, 2007, Skaug et al., 2009). The proteasome inhibitor bortezomib is
Cell cycle regulation
The cell cycle regulator p27 is regulated by proteasomal degradation (Pagano et al., 1995). It is upregulated by proteasome inhibition (Hussain et al., 2009), thereby blocking the normal progression of the cell cycle as well as the abnormal proliferation of cancer cells. In prostate epithelial cells, p27 is also upregulated by melatonin (Shiu et al., 2013). According to these investigators, the effect on p27 turnover is related to melatonin inhibition of NF-κB signaling. They argue that
Tumor suppressor factor p53
The tumor suppressor factor p53 is often reduced in cancer cells, facilitating tumor growth and drug regimen resistance. A major mechanism for reducing p53 is proteasomal degradation involving the E3 ligase, MDM2 (Momand et al., 1998). The proteasome inhibitor bortezomib results in accumulation of p53 in various types of cancer cells (Williams and McConkey, 2003, Lopes et al., 1997, Batchelor et al., 2009) including multiple myeloma, melanoma and chronic lymphocytic leukemia. Based on several
VEGF
Vascular endothelial growth factor (VEGF) is an important factor in solid tumor angiogenesis. Extracellular ubiquitin increases expression of VEGF (Steagall et al., 2013). Vlachostergios and Papandreou (2013) provided evidence that, in glioma, angiogenic NF-κB signaling is involved in the mechanism by which VEGF influences the growth of this malignant tumor.
Melatonin has been shown to have anti-angiogenic actions in endothelial cells in culture (Alvarez-Garcia et al., 2013), an effect
Apoptotic factors and the apoptosome
Regulation of apoptosis is an important cellular reaction in cancer cells. It is one of the mechanisms for the anti-tumor effects of the proteasome inhibitor bortezomib. Based on a review by Sainz et al. (2003) the process of bortezomib-induced apoptosis is described as initiated by inhibiting the destruction of pro-apoptotic proteins (such as Bax) by the proteasome.
A recent review described the major targets of proteasome inhibitors in cancer therapy (Crawford et al., 2011). These targets
Beta-catenin
Beta-catenin is another protein whose cellular levels are controlled by the ubiquitin–proteasome system (Aberle et al., 1997). It functions as a transcription factor but also as a cell adhesion molecule. It is involved in development of a number of solid tumors. It protects neurons from disorders associated with misfolded proteins (Jeong and Park, 2013). Melatonin has been reported to activate beta-catenin in osteoblastic cells (Park et al., 2011) and to increase beta-catenin levels in the
Melatonin and intracellular redox status
While some of the actions of melatonin involve classical membrane receptors, some are mediated by its ability to scavenge free radicals. As such the NCO structure in the side chain is considered to be an important functional group for this action (Tan et al., 2002). This structure, the amide group, a component of bortezomib (Kreidenweiss et al., 2008), is found adjacent to the pharmacophore. Lu and Wang (2013) have presented a model of the interaction of bortezomib with the B5 subunit of the
Phosphorylation of the proteasome — role for melatonin?
One mechanism for controlling proteasomes is phosphorylation of its subunits (116). Sha et al. (2011) provided evidence that phosphorylation of proteasome subunits enhances the activity of the proteasome. Proteasome subunits modified by phosphorylation include the Rpt2 and Rpt6 ATPases located in the Rpt ring in the base of the regulatory particle (see Fig. 3). The ATPases in this ring regulate such activities as protein substrate unfolding, gate opening, and translocation of proteins into the
Summary and conclusions
Melatonin and the proteasome inhibitor bortezomib share many cell signaling pathways, suggesting the hypothesis that melatonin is a proteasome inhibitor. The reactions of normal and cancer cells to proteasome inhibitors are not the same; some cancer cells are more sensitive to the actions of a proteasome inhibitor than normal cells; some cancer cells are also more sensitive to the antiproliferative and pro-apoptotic effects of melatonin than normal cells. Both bortezomib and melatonin inhibit
Author contributions
Both authors contributed to the article. J Vriend wrote the original draft.
Conflict of interest statement
The authors report no conflict of interest.
Acknowledgments
J Vriend acknowledges the University of Manitoba for granting him a sabbatical leave to work on this project. The authors received no funding for this project.
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