Endocrine-Disrupting Chemicals’ (EDCs) Effects on Tumour Microenvironment and Cancer Progression: Emerging Contribution of RACK1

Abstract

Endocrine disruptors (EDCs) can display estrogenic and androgenic effects, and their exposure has been linked to increased cancer risk. EDCs have been shown to directly affect cancer cell regulation and progression, but their influence on tumour microenvironment is still not completely elucidated. In this context, the signalling hub protein RACK1 (Receptor for Activated C Kinase 1) could represent a nexus between cancer and the immune system due to its roles in cancer progression and innate immune activation. Since RACK1 is a relevant EDCs target that responds to steroid-active compounds, it could be considered a molecular bridge between the endocrine-regulated tumour microenvironment and the innate immune system. We provide an analysis of immunomodulatory and cancer-promoting effects of different EDCs in shaping tumour microenvironment, with a final focus on the scaffold protein RACK1 as a pivotal molecular player due to its dual role in immune and cancer contexts.

Effects of Bisphenols on RACK1 Expression and Their Immunological Implications in THP-1 Cells

“…In line with this consideration, our previous data demonstrated that RACK1 basal expression is positively regulated by androgens and AR silencing induced a significant down-regulation of RACK1 expression ( Racchi et al, 2017 ). However, since BPA and other bisphenols are known to bind and activate different nuclear receptors, including GRα ( Prasanth et al, 2010 ; Zhang et al, 2017 ; Buoso et al, 2020c ) and that GR binding to RACK1 promoter induces its down-regulation ( Racchi et al, 2017 ), we cannot exclude GR involvement in the observed BPA-mediated effect on RACK1 expression. Therefore, to unmask AR-mediated BPA effects, we pre-treated THP-1 cells with mifepristone, a well-known GR inhibitor ( Bertagna et al, 1984 ), in order to exclude GR involvement and highlight BPA antagonistic activity for AR.…”

“…BPA is a diphenylmethane derivative that is used in the production of polycarbonate plastics and epoxy resins ( Monneret, 2017 ) and is known to have hormone-like, xenoestrogen and estrogen-mimicking properties ( Murata and Kang, 2018 ). Given its wide industrial use and these known endocrine-disrupting features, BPA exposure in humans has raised concerns, particularly for its possible influence on the immune system ( Buoso et al, 2020c ). Based on our previous data on the effects of EDCs on RACK1 expression and altered immune responses, we investigated the effects of BPA on RACK1 expression by reporter luciferase activity using the human RACK1 gene promoter, mRNA by qPCR, and protein levels by Western blotting.…”

“…Our published data show that RACK1 expression is tightly correlated with the production of pro-inflammatory cytokines IL-8 and TNF-α, which we previously demonstrated to be dependent on RACK1/PKCβ activation ( Corsini et al, 2021 ). In addition, we provided evidence for the existence of a complex hormonal balance, between glucocorticoids and androgens, in the control of RACK1 expression and immune cells activation, suggesting that RACK1 can be targeted by EDC ( Buoso et al, 2017a ; Buoso et al, 2017b ; Racchi et al, 2017 ; Buoso et al, 2020b ; Buoso et al, 2020c ). We demonstrated that glucocorticoid hormones decrease RACK1 expression while androgens and estrogens increase it ( Buoso et al, 2017a ; Buoso et al, 2017b ; Racchi et al, 2017 ; Buoso et al, 2020b ; Buoso et al, 2020c ).…”

“…In addition, we provided evidence for the existence of a complex hormonal balance, between glucocorticoids and androgens, in the control of RACK1 expression and immune cells activation, suggesting that RACK1 can be targeted by EDC ( Buoso et al, 2017a ; Buoso et al, 2017b ; Racchi et al, 2017 ; Buoso et al, 2020b ; Buoso et al, 2020c ). We demonstrated that glucocorticoid hormones decrease RACK1 expression while androgens and estrogens increase it ( Buoso et al, 2017a ; Buoso et al, 2017b ; Racchi et al, 2017 ; Buoso et al, 2020b ; Buoso et al, 2020c ). In this regard, some EDCs have been shown to have effects on RACK1, including the antiandrogens p,p’- dichlorodiphenyltrichloroethane ( p,p’- DDT) and p,p’ -dichlorodiphenyldichloroethylene ( p,p’ -DDE) ( Buoso et al, 2017a ), and the estrogen-active compounds diethylstilbestrol (DES) and zearalenone (ZEA) ( Buoso et al, 2020b ).…”

Identification of Potential Bisphenol A (BPA) Exposure Biomarkers in Ovarian Cancer

“…GPR30 plays a key role in the physiology of the reproductive system [ 16 , 17 ] and metabolism [ 18 ]. In the case of BPA, it has been shown to bind to multiple ERs including ERα, ERβ (cytoplasmic and membrane-bound), GPR30 and human nuclear receptor estrogen-related receptor gamma (ERRγ) [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”