The G protein-coupled estrogen receptor 1 (GPER-1) contributes to the proliferation and survival of mantle cell lymphoma cells

Rudelius, Martina; Rauert-Wunderlich, Hilka; Hartmann, Elena; Hoster, Eva; Dreyling, Martin; Klapper, Wolfram; Ott, German; Rosenwald, Andreas

doi:10.3324/haematol.2015.127399

Cited by 14 publications

(19 citation statements)

References 15 publications

(5 reference statements)

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“…IL17RB signaling may provide an additional source of NF-kB activation whereas GPER1 and IGF1 activate AKT1 and MAPK signaling in marginal zone lymphoma and WM, respectively. 44,51,52 However, WNT5A is a suppressor of B-cell proliferation. 53 Many of the genes upregulated in the MYD88 L265P CXCR4…”

Section: Discussionmentioning

confidence: 99%

Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

Hunter

Liu

Yang

et al. 2016

Blood

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• Transcription profiles associated with mutated MYD88, CXCR4, ARID1A, abnormal cytogenetics including 6q2, and familial WM are described.• Mutated CXCR4 profiles show impaired expression of the tumor suppressor response induced by MYD88 L265P and also G-protein/MAPK inhibitors.Whole-genome sequencing has identified highly prevalent somatic mutations including MYD88, CXCR4, and ARID1A in Waldenström macroglobulinemia (WM). The impact of these and other somatic mutations on transcriptional regulation in WM remains to be clarified. We performed next-generation transcriptional profiling in 57 WM patients and compared findings to healthy donor B cells. Compared with healthy donors, WM patient samples showed greatly enhanced expression of the VDJ recombination genes DNTT, RAG1, and RAG2, but not AICDA. Genes related to CXCR4 signaling were also upregulated and included CXCR4, CXCL12, and VCAM1 regardless of CXCR4 mutation status, indicating a potential role for CXCR4 signaling in all WM patients. The WM transcriptional profile was equally dissimilar to healthy memory B cells and circulating B cells likely due increased differentiation rather than cellular origin. The profile for CXCR4 mutations corresponded to diminished B-cell differentiation and suppression of tumor suppressors upregulated by MYD88 mutations in a manner associated with the suppression of TLR4 signaling relative to those mutated for MYD88 alone. Promoter methylation studies of top findings failed to explain this suppressive effect but identified aberrant methylation patterns in MYD88 wild-type patients. CXCR4 and MYD88 transcription were negatively correlated, demonstrated allele-specific transcription bias, and, along with CXCL13, were associated with bone marrow disease involvement. Distinct gene expression profiles for patients with wild-type MYD88, mutated ARID1A, familial predisposition to WM, chr6q deletions, chr3q amplifications, and trisomy 4 are also described. The findings provide novel insights into the molecular pathogenesis and opportunities for targeted therapeutic strategies for WM. (Blood. 2016;128(6):827-838)

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Section: Discussionmentioning

confidence: 99%

Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

Hunter

Liu

Yang

et al. 2016

Blood

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“…However, the role of GPER-1 in cancer remains controversial. There are a variety of in vitro studies reporting oncogenic features of this gene, like activation of cancer cell proliferation (Jiang et al 2015;Luo et al 2014;Rudelius et al 2015;Scaling et al 2014), whereas other groups observed inhibitory effects of GPER-1 on tumor cells (Sathya et al 2015;Skrzypczak et al 2013;Wang et al 2012;Weißenborn et al 2014a, b). With regard to GPER-1 correlation with clinical outcome of cancer patients, some groups report a beneficial role of this receptor (Ignatov et al 2013b;Martin et al 2018), and others did not observe any effect on patients survival (Kolkova et al 2012), or found this receptor to have adverse effects on survival (Fujiwara et al 2012;Zhu et al 2018).…”

Section: Introductionmentioning

confidence: 99%

G protein-coupled estrogen receptor 1 (GPER-1) and agonist G-1 inhibit growth of ovarian cancer cells by activation of anti-tumoral transcriptome responses: impact of GPER-1 mRNA on survival

Schüler-Toprak¹,

Skrzypczak

Ignatov³

et al. 2020

J Cancer Res Clin Oncol

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Purpose The present study intended to further elucidate the role of G protein-coupled estrogen receptor 1 (GPER-1) in ovarian cancer by comparing the effects of a GPER-1 knockdown and treatment with its agonist G-1 on cell growth, apoptosis, and the transcriptome of two ovarian cancer cell lines. Furthermore, the role of GPER-1 in ovarian cancer survival was examined. Methods GPER-1 expression in OVCAR-3 and OAW-42 ovarian cancer cells was knocked down by RNAi. The effects on cell growth were measured by means of the fluorimetric cell titer blue assay and on the transcriptome by Affymetrix GeneChip analysis. The effect of GPER-1 on patient's survival was examined using open source mRNA and clinical data of 1657 ovarian cancer patients. Results GPER-1 knockdown resulted in a significant growth stimulation of both cell lines, whereas treatment with agonist G-1 decreased growth of both cell lines in a dose-dependent manner. Transcriptome analyses revealed a set of 18 genes being conversely regulated after GPER-1 knockdown and G-1 treatment. Generally, treatment with G-1 led to a transcriptome response associated with growth inhibition. In contrast, knockdown of GPER-1 exerted opposite effects, stimulating pathways activating mitosis, but inhibiting pathways associated with apoptosis or interferon signaling. Further analyses using open-access mRNA and clinical data by bioinformatical online tools revealed a longer OS (HR = 0.86, p = 0.057) and PFS (HR = 0.81, p = 0.0035) of ovarian cancer patients with high GPER-1 mRNA expression. Conclusions The results of this study clearly support the hypothesis that GPER-1 acts as a tumor suppressor in ovarian cancer.

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“…Although ERα and ERβ are known to be expressed in immune cells and some lymphomas, the information available on GPER expression in lymphoid cells is limited. Recently, it was reported that GPER contribute to the proliferation and survival of mantle cell lymphoma cells . It has also been proposed that GPER regulates CXCR4 signaling in pre‐B cell ALL .…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells

Torres-López

Maycotte

Liñán-Rico

et al. 2019

Journal of Leukocyte Biology

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Estrogens demonstrate biological activity in numerous organ systems, including the immune system, and exert their effects through estrogen receptors (ER) of two types: intracellular ERα and ERβ that activate transcriptional factors and membrane G protein‐coupled ER GPER. The latter is capable to mediate fast activation of cytosolic signaling pathways, influencing transcriptional events in response to estrogens. Tamoxifen (TAM), widely used in chemotherapy of ERα‐positive breast cancer, is considered as an ERα antagonist and GPER agonist. TAM was shown to possess “off‐target” cytotoxicity, not related to ER in various tumor types. The present work was designed to study biological effects of TAM on the glucocorticoid (GC)‐resistant cell line Jurkat, derived from acute lymphoblastic leukemia of T lineage (T‐ALL). We have shown that T‐ALL cell lines, in contrast to healthy T cells, express only GPER, but not ERα or ERβ. TAM compromised mitochondrial function and reduced the viability and proliferation of Jurkat cells. Additionally, TAM induced autophagy in a GPER‐dependent manner. Gene expression profiling revealed the up‐regulation of autophagy‐related gene ATG5. Interestingly, TAM sensitized Jurkat cells to dexamethasone (DEX) treatment, which may be related to its capacity to cause autophagy. We suggest that TAM‐based adjuvant therapy may represent a novel strategy in T‐ALL patients handling.

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The G protein-coupled estrogen receptor 1 (GPER-1) contributes to the proliferation and survival of mantle cell lymphoma cells

Cited by 14 publications

References 15 publications

Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

G protein-coupled estrogen receptor 1 (GPER-1) and agonist G-1 inhibit growth of ovarian cancer cells by activation of anti-tumoral transcriptome responses: impact of GPER-1 mRNA on survival

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells

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