Abstract
The estrogen-related receptors (ERRs) are important members of nuclear receptors which contain three isoforms (α, β, and γ). ERRα is the best-characterized isoform expressed mainly in high-energy demanding tissues where it preferentially works in association with the peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) and PGC-1β. ERRα together with its cofactors modulates cellular metabolism, supports the growth of rapidly dividing cells, directs metabolic programs required for cell differentiation and maintains cellular energy homeostasis in differentiated cells. In cancer cells, the functional association between ERRα and PGC-1s is further influenced by oncogenic signals and induces metabolic programs favoring cell growth and proliferation as well as tumor progression. Recently, cholesterol has been identified as a natural ERRα ligand using a combined biochemical strategy. This new finding highlighted some important physiological aspects related to the use of cholesterol-lowering drugs such as statins and bisphosphonates. Even more meaningful is the link between increased cholesterol levels and certain cancer phenotypes characterized by an overexpressed ERRα such as mammary, prostatic, and colorectal cancers, where the metabolic adaptation affects many cancer processes. Moreover, high-energy demanding cancer-related processes are strictly related to the cross-talk between tumor cells and some key players of tumor microenvironment, such as tumor-associated macrophage that fuels cancer progression. Some evidence suggests that high cholesterol content and ERRα activity favor the inflammatory environment by the production of different cytokines. In this review, starting from the most recent observations on the physiological role of the new signaling activated by the natural ligand of ERRα, we propose a new hypothesis on the suitability to control cholesterol levels as a chance in modulating ERRα activity in those tumors in which its expression and activity are increased.
Highlights
Specialty section: This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology
The existence of a direct correlation between the levels of cholesterol and the production of IL-8 in the macrophage suggests some interesting hypotheses that could represent the rational basis for further studies: (a) the agonistic action of cholesterol on ERRα in CRC cells could favor the recruitment of co-regulators involved in the enhancement of IL-8 gene expression; (b) a similar mechanism could occur in macrophages leading the way for new hypotheses on ERRα involvement in the regulation of the inflammatory process within the tumor microenvironment
The ERRα transcriptional activity in normal cells is directed to modulate cellular metabolism, supporting the growth of rapidly dividing cells and to control metabolic programs required for cellular energy homeostasis in differentiated cells and to satisfy energy request during cell differentiation
Summary
Nuclear receptors (NRs) are a large family of transcription factors that are activated by different signal molecules such as steroids, thyroid hormones, vitamins, retinoic acid, oxysterols, and many other metabolites [1]. NRs together with a multitude of co-factors, drive transcription of genes that control cell proliferation, development, reproduction, and different metabolic phenomena upon which those processes are strictly dependent. A proper functional control of energy pathways within the cells is supported by the coordination of several transcription factors, including NRs, and associated co-factors. Many members of NR superfamily are involved in these processes since they can activate a specific gene expression network in response to hormonal, nutrient, and metabolite signals coming from distinct physiological (or pathological) conditions [2]
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