The scaffold protein RACK1 is a target of endocrine disrupting chemicals (EDCs) with important implication in immunity

Buoso, Erica; Galasso, Marilisa; Ronfani, Melania; Papale, Angela; Galbiati, Valentina; Eberini, Ivano; Marinovich, Marina; Racchi, Marco; Corsini, Emanuela

doi:10.1016/j.taap.2017.04.011

Cited by 22 publications

(32 citation statements)

References 55 publications

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“…It is therefore critical to understand the molecular mechanism through which cortisol and DHEA regulate RACK1 expression, especially considering the central role of RACK1 in cellular homeostasis. Indeed, changes in RACK1 levels are likely to subvert physiological functions, which go far beyond the immune system, possibly affecting tumor progression as demonstrated by the opposing effects of nandrolone and p,p′DDE on THP-1 cell proliferation [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, treatment with the AR agonist nandrolone resulted in a dose-related increase in luciferase activity and consequently in RACK1 expression. These findings suggest that RACK1 could be a relevant target of EDCs, responding in an opposing manner to agonists or antagonists of the AR and representing a bridge between the endocrine system and the innate immune system [ 56 ].…”

Section: Effect Of Androgens In Dhea-induced Rack1 Expressionmentioning

confidence: 99%

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Role of Hormones in the Regulation of RACK1 Expression as a Signaling Checkpoint in Immunosenescence

Racchi

Buoso

Ronfani

et al. 2017

IJMS

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Abstract:Immunosenescence defines the decline in immune function that occurs with aging. This has been associated, at least in part, with defective cellular signaling via protein kinase C (PKC) signal transduction pathways. Our data suggest reduced PKC activation and consequently reduced response to lipopolysaccharide (LPS) stimulation and cytokine release. The lack of PKC activation seems to be dependent on the reduced expression of the receptor for activated C kinase 1 (RACK1), a scaffolding protein involved in multiple signal transduction cascades. The defective expression of RACK1 may be dependent on age-related alteration of the balance between the adrenal hormones cortisol and dehydroepiandrosterone (DHEA). DHEA levels reduce with aging, while cortisol levels remain substantially unchanged, resulting in an overall increase in the cortisol:DHEA ratio. These hormonal changes are significant in the context of RACK1 expression and signaling function because DHEA administration in vivo and in vitro can restore the levels of RACK1 and the function of the PKC signaling cascade in aged animals and in human cells. In contrast, there is evidence that cortisol can act as a negative transcriptional regulator of RACK1 expression. The rack1 gene promoter contains a glucocorticoid responsive element that is also involved in androgen signaling. Furthermore DHEA may have an indirect influence on the post-transcriptional regulation of the functions of the glucocorticoid receptor. In this review, we will examine the role of the hormonal regulation of rack1 gene transcriptional regulation and the consequences on signaling and function in immune cells and immunosenescence.

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Androgens In Dhea-induced Rack1 Expressionmentioning

confidence: 99%

Role of Hormones in the Regulation of RACK1 Expression as a Signaling Checkpoint in Immunosenescence

Racchi

Buoso

Ronfani

et al. 2017

IJMS

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“…Hence, they recognise a response element usually described as a canonical androgen/glucocorticoid response element (ARE/GRE) characterised by a well-conserved 5 -hexamer and a less stringent sequence requirement for the 3 -hexamer. Therefore, the GRE sequence described in the RACK1 gene promoter is also a cis-regulatory target of AR [17,18,20] as further confirmed by nandrolone induced-RACK1 expression and the immune response [18]. These data demonstrate that a complex hormonal balance, between cortisol and androgens, can regulate RACK1 expression and immune activation [20] thus supporting RACK1 as a possible target of EDCs with a consequent modulation of innate immune functionality and cell proliferation [16,18].…”

Section: Rack1 As a Possible Target Of Edcsmentioning

confidence: 62%

“…In addition, DES exposure has also been correlated with obesity [30] and increased risk of prostate and testicular cancer [31]. While DDT and DDE effects are correlated with their weak and strong AR antagonist profile respectively, DES is characterised by an oestrogenic activity displayed by its binding to oestrogen receptor (ER) [18,19] change.…”

Section: Edcs' Molecular Mechanisms: From Dichlorodiphenyltrichloroetmentioning

confidence: 99%

“…The role of EDCs in modulating the tumour microenvironment has not been elucidated, but is of pivotal interest. In this regard, the scaffold protein Receptor for Activated C Kinase 1 (RACK1) is an EDC target in the immune context [17][18][19][20] and an important molecular player for cancer progression (reviewed in [21]). Therefore, EDCs-mediated RACK1 regulation in both contexts could be central to understand the role of endocrine-mediated microenvironment regulation and to link innate immune activation with cancer progression through RACK1.…”

Section: Introductionmentioning

confidence: 99%

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

Buoso

Masi

Racchi

et al. 2020

IJMS

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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.

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Role of Protein Kinase C in Immune Cell Activation and Its Implication Chemical-Induced Immunotoxicity

Corsini

Buoso

Galbiati

et al. 2021

Advances in Experimental Medicine and Biology

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The scaffold protein RACK1 is a target of endocrine disrupting chemicals (EDCs) with important implication in immunity

Cited by 22 publications

References 55 publications

Role of Hormones in the Regulation of RACK1 Expression as a Signaling Checkpoint in Immunosenescence

Role of Hormones in the Regulation of RACK1 Expression as a Signaling Checkpoint in Immunosenescence

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

Role of Protein Kinase C in Immune Cell Activation and Its Implication Chemical-Induced Immunotoxicity

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