Cholesterol as an Endogenous ERRα Agonist: A New Perspective to Cancer Treatment

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.

Differential protective effects of bisphosphonates and denosumab on primary breast cancer risk, potentially to be modified by statins: a retrospective study using electronic health records

“…All the cohort and case control studies which focused on the relationship of bisphosphonates and breast cancer did not separate statins use from control group either [15][16][17][18][19][20][21][22][23]. In our study, statins showed similar breast cancer protective effect as bisphosphonates in consistence with published preclinical research [11][12][13]. It is possible that the comparable breast cancer protective effect of bisphosphonates or statins might be masked when the control group has comedication of either of these two drugs.…”

“…ERRα plays roles in osteoporosis and breast cancer development. ERRα transcriptional activity is enhanced by cholesterol and suppressed by statins and bisphosphonates [11][12]. Meanwhile, the epigenetic impacts of statin and bisphosphonates on DNA methylation, histone deacetylation and microRNAs occurring in normal cells could be both cancer preventing and promoting [13].…”

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases

“…Recent studies suggest that endogenous cholesterols may be potential ESRRA ligands [31,53]. Moreover, PPARGC1A increases cholesterol-ESRRA interaction and cholesterol stabilizes the ESRRA-PPARGC1A complex [53,54].…”

“…Similarly, increasing the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), the protein ligand of ESRRA, increases energy expenditure and reduces obesity [23]. So far, most previous studies of ESRR actions have focused on its role in cancer progression and this topic has been reviewed elsewhere [24][25][26][27][28][29][30][31][32][33][34][35]. There have also been a few studies on its roles in bone and muscle differentiation [36][37][38], trauma/shock [39], and infection [40].…”

Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy

“…As stated above, cholesterol can also act as a functional and endogenous agonist of , which has important roles in cancer, fatty acid metabolism, skeletal homeostasis, as well as mitochondria biogenesis and function (17,18). In addition to the above processes, cholesterol is a major regulator of lipid organization, being responsible for the close packing of acyl chains of phospholipids, promoting phase separation and stabilizing the formation of cholesterol and sphingolipid-rich membrane microdomains known as lipid rafts or membrane rafts (19,20), which constitute centers of organization for signal transduction and trafficking in normal and cancer cells (21-23).…”