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Cells
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Nuclear Receptor Signaling and Cancer
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Nuclear Receptor Signaling and Cancer

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 16292

Special Issue Editor

Prof. Dr. Guan Chen

E-Mail Website
Guest Editor
Medical College of Wisconsin, Milwaukee, WI, USA
Interests: regulation of nuclear receptors in human cancer treatment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nuclear receptors (NRs) are a family of transcriptional factors that play a critical role in physiological processes such as reproduction and bone metabolism. NRs are involved in signaling in both nuclear and nonnuclear compartments in response to ligands, growth factors, cytokines, and others, through their crosstalk as well as interaction with other major signal transduction pathways. As a result, NRs convert various extracellular signals into gene expression and various other cellular outcomes, such as cell growth, differentiation, and cell death by environmentally dependent mechanisms.

NRs are involved in every step of cancer, from cancer initiation to cancer growth and further to cancer metastasis and/or clinic prognosis. Moreover, different NRs can cooperate or antagonize the regulation of tumor growth, and the same NRs in different tissues may have a growth-promoting or growth-inhibitory activity dependent or independent of ligands. This Special Issue of Cells welcomes original research papers and review articles in these rapidly developing fields, with the tentative title “Nuclear Receptor Signaling and Cancer”. We hope that this Special Issue will serve as a platform to improve our appreciation of the fascinating roles of NRs in cancer.

Prof. Guan Chen
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • nuclear receptors
  • signal transduction
  • cancer prevention and therapy
  • crosstalk of nuclear receptors
  • interaction of nuclear receptors with other pathways

Published Papers (5 papers)

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Research

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12 pages, 1139 KiB  
Article
Investigating the Role of Methylation in Silencing of VDR Gene Expression in Normal Cells during Hematopoiesis and in Their Leukemic Counterparts
by Urszula Nowak, Sylwia Janik, Aleksandra Marchwicka, Agnieszka Łaszkiewicz, Agnieszka Jakuszak, Małgorzata Cebrat and Ewa Marcinkowska
Cells 2020, 9(9), 1991; https://doi.org/10.3390/cells9091991 - 29 Aug 2020
Cited by 5 | Viewed by 2464
Abstract
(1) Background: Vitamin D receptor (VDR) is present in multiple types of blood cells, and its ligand, 1,25-dihydroxyvitamin D (1,25D), is important for the proper functioning of the immune system. Activity of VDR is higher in hematopoietic stem and progenitor cells than [...] Read more.
(1) Background: Vitamin D receptor (VDR) is present in multiple types of blood cells, and its ligand, 1,25-dihydroxyvitamin D (1,25D), is important for the proper functioning of the immune system. Activity of VDR is higher in hematopoietic stem and progenitor cells than in fully differentiated blood cells of mice and humans. In some human acute myeloid leukemia (AML) blasts, the expression of the VDR gene is also high. The mechanism of silencing the VDR gene expression during differentiation of blood cells has been addressed in this work. (2) Methods: The cells have been obtained using fluorescence activated sorting from murine tissues and from human umbilical cord blood (UCB). Then, the expression of the VDR gene and transcriptional activity of the VDR protein has been tested in real-time polymerase chain reaction (PCR). Eventually, the methylation of VDR promoter regions was tested using bisulfite sequencing. (3) Results: The CpG islands in VDR promoters were not methylated in the cells studied both in mice and in humans. The use of hypomethylating agents had no effect toward expression of human VDR transcripts, but it increased expression of the VDR-target gene, CYP24A1. (4) Conclusions: The expression of the VDR gene and transcriptional activity of the VDR protein varies at successive stages of hematopoietic differentiation in humans and mice, and in blasts from AML patients. The experiments presented in this case indicate that methylation of the promoter region of the VDR gene is not the major mechanism responsible for these differences. Full article
(This article belongs to the Special Issue Nuclear Receptor Signaling and Cancer)
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22 pages, 7084 KiB  
Article
The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells
by Jin Xu, Xi Yang, Dhanraj Deshmukh, Hegang Chen, Shengyun Fang and Yun Qiu
Cells 2020, 9(5), 1094; https://doi.org/10.3390/cells9051094 - 28 Apr 2020
Cited by 10 | Viewed by 3217
Abstract
Background: Drug resistance is one of the most prevalent causes of death in advanced prostate cancer patients. Combination therapies that target cancer cells via different mechanisms to overcome resistance have gained increased attention in recent years. However, the optimal drug combinations and the [...] Read more.
Background: Drug resistance is one of the most prevalent causes of death in advanced prostate cancer patients. Combination therapies that target cancer cells via different mechanisms to overcome resistance have gained increased attention in recent years. However, the optimal drug combinations and the underlying mechanisms are yet to be fully explored. Aim and methods: The aim of this study is to investigate drug combinations that inhibit the growth of drug-resistant cells and determine the underlying mechanisms of their actions. In addition, we also established cell lines that are resistant to combination treatments and tested new compounds to overcome the phenomenon of double drug-resistance. Results: Our results show that the combination of enzalutamide (ENZ) and docetaxel (DTX) effectively inhibit the growth of prostate cancer cells that are resistant to either drug alone. The downregulation of transcription factor E2F1 plays a crucial role in cellular inhibition in response to the combined therapy. Notably, we found that the androgen receptor (AR) variant AR3 (a.k.a. AR-V7), but not AR full length (AR-FL), positively regulates E2F1 expression in these cells. E2F1 in turn regulates AR3 and forms a positive regulatory feedforward loop. We also established double drug-resistant cell lines that are resistant to ENZ+DTX combination therapy and found that the expression of both AR3 and E2F1 was restored in these cells. Furthermore, we identified that auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, overcame drug resistance and inhibited the growth of drug-resistant prostate cancer cells both in vitro and in vivo. Conclusion and significance: This proof-of-principle study demonstrates that targeting the E2F1/AR3 feedforward loop via a combination therapy or a multi-targeting drug could circumvent castration resistance in prostate cancer. Full article
(This article belongs to the Special Issue Nuclear Receptor Signaling and Cancer)
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15 pages, 1611 KiB  
Article
AR/ER Ratio Correlates with Expression of Proliferation Markers and with Distinct Subset of Breast Tumors
by Nelson Rangel, Milena Rondon-Lagos, Laura Annaratone, Andrés Felipe Aristizábal-Pachon, Paola Cassoni, Anna Sapino and Isabella Castellano
Cells 2020, 9(4), 1064; https://doi.org/10.3390/cells9041064 - 24 Apr 2020
Cited by 20 | Viewed by 3099
Abstract
The co-expression of androgen (AR) and estrogen (ER) receptors, in terms of higher AR/ER ratio, has been recently associated with poor outcome in ER-positive (ER+) breast cancer (BC) patients. The aim of this study was to analyze if the biological aggressiveness, underlined in [...] Read more.
The co-expression of androgen (AR) and estrogen (ER) receptors, in terms of higher AR/ER ratio, has been recently associated with poor outcome in ER-positive (ER+) breast cancer (BC) patients. The aim of this study was to analyze if the biological aggressiveness, underlined in ER+ BC tumors with higher AR/ER ratio, could be due to higher expression of genes related to cell proliferation. On a cohort of 47 ER+ BC patients, the AR/ER ratio was assessed by immunohistochemistry and by mRNA analysis. The expression level of five gene proliferation markers was defined through TaqMan®-qPCR assays. Results were validated using 979 BC cases obtained from gene expression public databases. ER+ BC tumors with ratios of AR/ER ≥ 2 have higher expression levels of cellular proliferation genes than tumors with ratios of AR/ER < 2, in both the 47 ER+ BC patients (P < 0.001) and in the validation cohort (P = 0.005). Moreover, BC cases with ratios of AR/ER ≥ 2 of the validation cohort were mainly assigned to luminal B and HER2-enriched molecular subtypes, typically characterized by higher proliferation and poorer prognosis. These data suggest that joint routine evaluation of AR and ER expression may identify a unique subset of tumors, which show higher levels of cellular proliferation and therefore a more aggressive behavior. Full article
(This article belongs to the Special Issue Nuclear Receptor Signaling and Cancer)
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14 pages, 1795 KiB  
Article
PlexinB1 Promotes Nuclear Translocation of the Glucocorticoid Receptor
by Magali Williamson, Ritu Garg and Claire M. Wells
Cells 2020, 9(1), 3; https://doi.org/10.3390/cells9010003 - 18 Dec 2019
Cited by 7 | Viewed by 3746
Abstract
Androgen receptor (AR) and glucocorticoid receptor (GR) are nuclear receptors whose function depends on their entry into the nucleus where they activate transcription of an overlapping set of genes. Both AR and GR have a role in resistance to androgen deprivation therapy (ADT), [...] Read more.
Androgen receptor (AR) and glucocorticoid receptor (GR) are nuclear receptors whose function depends on their entry into the nucleus where they activate transcription of an overlapping set of genes. Both AR and GR have a role in resistance to androgen deprivation therapy (ADT), the mainstay of treatment for late stage prostate cancer. PlexinB1, a receptor for semaphorins, has been implicated in various cancers including prostate cancer and has a role in resistance to ADT. We show here that activation of PlexinB1 by Sema4D and Sema3C results in translocation of endogenous GR to the nucleus in prostate cancer cells, and that this effect is dependent on PlexinB1 expression. Sema4D/Sema3C promotes the translocation of GR-GFP to the nucleus and mutation of the nuclear localization sequence (NLS1) of GR abrogates this response. These findings implicate the importin α/β system in the Sema4D/Sema3C-mediated nuclear import of GR. Knockdown of PlexinB1 in prostate cancer cells decreases the levels of glucocorticoid-responsive gene products and antagonizes the decrease in cell motility and cell area of prostate cancer cells upon dexamethasone treatment, demonstrating the functional significance of these findings. These results show that PlexinB1 activation has a role in the trafficking and activation of the nuclear receptor GR and thus may have a role in resistance to androgen deprivation therapy in late stage prostate cancer. Full article
(This article belongs to the Special Issue Nuclear Receptor Signaling and Cancer)
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Review

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16 pages, 304 KiB  
Review
Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia
by Pan Pan and Xiao Chen
Cells 2020, 9(9), 1921; https://doi.org/10.3390/cells9091921 - 19 Aug 2020
Cited by 13 | Viewed by 2878
Abstract
The nuclear receptor (NR) superfamily has been studied extensively in many solid tumors and some receptors have been targeted to develop therapies. However, their roles in leukemia are less clear and vary considerably among different types of leukemia. Some NRs participate in mediating [...] Read more.
The nuclear receptor (NR) superfamily has been studied extensively in many solid tumors and some receptors have been targeted to develop therapies. However, their roles in leukemia are less clear and vary considerably among different types of leukemia. Some NRs participate in mediating the differentiation of myeloid cells, making them attractive therapeutic targets for myeloid leukemia. To date, the success of all-trans retinoic acid (ATRA) in treating acute promyelocytic leukemia (APL) remains a classical and unsurpassable example of cancer differentiation therapy. ATRA targets retinoic acid receptor (RAR) and forces differentiation and/or apoptosis of leukemic cells. In addition, ligands/agonists of vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) have also been shown to inhibit proliferation, induce differentiation, and promote apoptosis of leukemic cells. Encouragingly, combining different NR agonists or the addition of NR agonists to chemotherapies have shown some synergistic anti-leukemic effects. This review will summarize recent research findings and discuss the therapeutic potential of selected NRs in acute and chronic myeloid leukemia, focusing on RAR, VDR, PPAR, and retinoid X receptor (RXR). We believe that more mechanistic studies in this field will not only shed new lights on the roles of NRs in leukemia, but also further expand the clinical applications of existing therapeutic agents targeting NRs. Full article
(This article belongs to the Special Issue Nuclear Receptor Signaling and Cancer)
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