Nuclear receptors: Lipid and hormone sensors with essential roles in the control of cancer development

Font-Díaz, Joan; Jiménez-Panizo, Alba; Caelles, Carmé; Vivanco, María dM.; Pérez, Paloma; Aranda, Ana; Estébanez‐Perpiñá, Eva; Castrillo, Antonio; Ricote, Mercedes; Valledor, Annabel F.

doi:10.1016/j.semcancer.2020.12.007

Cited by 31 publications

(21 citation statements)

References 247 publications

(321 reference statements)

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“…Although both RORs and LXRs are considered as sensors of specific lipids, LXRs generally play a tumor-suppressive role in several types of cancer, including prostate cancer [3,15,38]. Although our current study is focused on the role of RORγ in control of LXR-mediated cholesterol efflux program, it is possible that their crosstalk may also occur at other pathways such as cell cycle, apoptosis, and oncogenic kinase signaling which appear to be the targets of LXR agonists [38]. Interestingly, RORγ and LXRs are both major players in tumor immune microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Yang

Huang

et al. 2022

Cancers

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Metastatic castration-resistant prostate cancer (mCRPC) features high intratumoral cholesterol levels, due to aberrant regulation of cholesterol homeostasis. However, the underlying mechanisms are still poorly understood. The retinoid acid receptor-related orphan receptor gamma (RORγ), an attractive therapeutic target for cancer and autoimmune diseases, is strongly implicated in prostate cancer progression. We demonstrate in this study that in mCRPC cells and tumors, RORγ plays a crucial role in deregulation of cholesterol homeostasis. First, we found that RORγ activates the expression of key cholesterol biosynthesis proteins, including HMGCS1, HMGCR, and SQLE. Interestingly, we also found that RORγ inhibition induces cholesterol efflux gene program including ABCA1, ABCG1 and ApoA1. Our further studies revealed that liver X receptors (LXRα and LXRβ), the master regulators of cholesterol efflux pathway, mediate the function of RORγ in repression of cholesterol efflux. Finally, we demonstrated that RORγ antagonist in combination with statins has synergistic effect in killing mCRPC cells through blocking statin-induced feedback induction of cholesterol biosynthesis program and that the combination treatment also elicits stronger anti-tumor effects than either alone. Altogether, our work revealed that in mCRPC, RORγ contributes to aberrant cholesterol homeostasis by induction of cholesterol biosynthesis program and suppression of cholesterol efflux genes. Our findings support a therapeutic strategy of targeting RORγ alone or in combination with statin for effective treatment of mCRPC.

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Section: Discussionmentioning

confidence: 99%

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Yang

Huang

et al. 2022

Cancers

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“…PPARs have well known anti-tumourogenic effects [ 8 ]. PPARα activation can induce apoptosis and tumour cell death, preventing tumour expansion and inflammation.…”

Section: The Pparα and Pparγ Epigenetic Landscape In Diseasementioning

confidence: 99%

“…PPARs regulate energy metabolism and inflammation, exerting anti-fibrotic and anti-inflammatory effects in diverse conditions, including cancer, autoimmune diseases, liver steatosis, and type 2 diabetes (T2D) [ 8 , 9 , 10 ]. PPARs stimulate the expression of anti-inflammatory molecules and inhibit the production of extracellular matrix proteins and pro-inflammatory cytokines, as well as modulating the response and phenotype of immune cells such as macrophages and lymphocytes [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

The PPARα and PPARγ Epigenetic Landscape in Cancer and Immune and Metabolic Disorders

Porcuna

Martínez

Ricote

2021

IJMS

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Peroxisome proliferator-activated receptors (PPARs) are ligand-modulated nuclear receptors that play pivotal roles in nutrient sensing, metabolism, and lipid-related processes. Correct control of their target genes requires tight regulation of the expression of different PPAR isoforms in each tissue, and the dysregulation of PPAR-dependent transcriptional programs is linked to disorders, such as metabolic and immune diseases or cancer. Several PPAR regulators and PPAR-regulated factors are epigenetic effectors, including non-coding RNAs, epigenetic enzymes, histone modifiers, and DNA methyltransferases. In this review, we examine advances in PPARα and PPARγ-related epigenetic regulation in metabolic disorders, including obesity and diabetes, immune disorders, such as sclerosis and lupus, and a variety of cancers, providing new insights into the possible therapeutic exploitation of PPAR epigenetic modulation.

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“…Furthermore, inflammation also regulates the processes of intravasation and extravasation that are essential in the metastatic spread, via the expression of a set of adhesion molecules, integrins, inflammatory cytokines and growth factors like Vascular Endothelial Growth Factors (VEGF), among others ( 43 ). Different groups have demonstrated that TRs modulate progression and/or metastasis of different tumors through several mechanisms, mostly of which are connected to the inflammatory pathways activated in the tumoral environment ( 90 ). Among them, TRβ can inhibit tumor cell migration, invasion and metastasis in both cellular and animal models of HCC and breast cancer by antagonizing the actions of the TGFβ pathway ( 94 , 109 ), which induces EMT in a p38MAPK-dependent manner in some tumors ( 110 ).…”

Section: Introductionmentioning

confidence: 99%

Thyroid hormones act as modulators of inflammation through their nuclear receptors

Lasa

Contreras‐Jurado

2022

Front. Endocrinol.

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Reciprocal crosstalk between endocrine and immune systems has been well-documented both in physiological and pathological conditions, although the connection between the immune system and thyroid hormones (THs) remains largely unclear. Inflammation and infection are two important processes modulated by the immune system, which have profound effects on both central and peripheral THs metabolism. Conversely, optimal levels of THs are necessary for the maintenance of immune function and response. Although some effects of THs are mediated by their binding to cell membrane integrin receptors, triggering a non-genomic response, most of the actions of these hormones involve their binding to specific nuclear thyroid receptors (TRs), which generate a genomic response by modulating the activity of a great variety of transcription factors. In this special review on THs role in health and disease, we highlight the relevance of these hormones in the molecular mechanisms linked to inflammation upon their binding to specific nuclear receptors. In particular, we focus on THs effects on different signaling pathways involved in the inflammation associated with various infectious and/or pathological processes, emphasizing those mediated by NF-kB, p38MAPK and JAK/STAT. The findings showed in this review suggest new opportunities to improve current therapeutic strategies for the treatment of inflammation associated with several infections and/or diseases, such as cancer, sepsis or Covid-19 infection.

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Nuclear receptors: Lipid and hormone sensors with essential roles in the control of cancer development

Cited by 31 publications

References 247 publications

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

The PPARα and PPARγ Epigenetic Landscape in Cancer and Immune and Metabolic Disorders

Thyroid hormones act as modulators of inflammation through their nuclear receptors

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