Cytoplasmic location of NR4A1 in aggressive lymphomas is associated with a favourable cancer specific survival

Fechter, Karoline; Feichtinger, Julia; Prochazka, Katharina; Unterluggauer, Julia Judith; Pansy, Katrin; Steinbauer, Elisabeth; Pichler, Martin; Haybaeck, Johannes; Prokesch, Andreas; Greinix, Hildegard; Beham‐Schmid, Christine; Neumeister, Peter; Thallinger, Gerhard G.; Deutsch, Alexander

doi:10.1038/s41598-018-32972-4

Cited by 5 publications

(6 citation statements)

References 64 publications

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“…By using the Hans algorithm [5], all cases were classified as follows: 46 cases were categorized as GCB-DLBCL and 25 as NGCB-DLBCL. Determination of the IHC profiles according to the Hans algorithm has previously been described by Fechter et al [59]. As transformed DLBCL samples originating from FLs exhibited a similar expression pattern as GCB-DLCBL samples [60], these samples were added to this subtype.…”

Section: Methodsmentioning

confidence: 99%

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Pansy

Feichtinger

Ehall

et al. 2019

IJMS

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In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

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Section: Methodsmentioning

confidence: 99%

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Pansy

Feichtinger

Ehall

et al. 2019

IJMS

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“…This interaction activates a death inducing signaling complex which catalyzes procaspase-8. Cleaved caspase-8 activates effector caspases which cause cell death by damaging the nucleus and other internal organelle [139,140,141].…”

Section: Apoptosismentioning

confidence: 99%

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

Herring

Elison

Tessem

2019

Cells

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The Nr4a family of nuclear hormone receptors is composed of three members—Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.

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“…Moreover, GSEA conducted between the NR4A1 high and low groups revealed that high mRNA levels of NR4A1 are correlated with the negative regulation of MAPK cascade ( Figure S6A,B ). Furthermore, previous studies have reported that cytoplasmic NR4A1 is associated with ERK signaling and a good prognosis [ 36 ]. This evidence raises the possibility that NR4A1 genes may contribute to the negative regulation of the ERK signaling pathway in breast cancer.…”

Section: Resultsmentioning

confidence: 99%

“…According to previous reports, cytoplasmic NR4A1 is associated with the ERK signaling pathway [ 36 ]. ERK signaling is a pathway that plays a crucial role in tamoxifen resistance as well as cellular signaling in various cancers, including breast cancer [ 26 ].…”

Section: Discussionmentioning

confidence: 97%

NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer

Kim

et al. 2021

Cells

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Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.

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Cytoplasmic location of NR4A1 in aggressive lymphomas is associated with a favourable cancer specific survival

Cited by 5 publications

References 64 publications

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer

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