Expression of the serotonin receptor 2B in uveal melanoma and effects of an antagonist on cell lines

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.

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Depsipeptide (FR901228) Inhibits Proliferation and Induces Apoptosis in Primary and Metastatic Human Uveal Melanoma Cell Lines

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.02-1052 ◽

2003 ◽

Vol 44 (6) ◽

pp. 2390 ◽

Cited By ~ 31

Author(s):

Dino D. Klisovic ◽

Steven E. Katz ◽

David Effron ◽

Marko I. Klisovic ◽

Joseph Wickham ◽

...

Keyword(s):

Cell Lines ◽

Uveal Melanoma ◽

Melanoma Cell ◽

Uveal Melanoma Cell ◽

Melanoma Cell Lines

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176 Serotonin receptor 2b (5-ht2b) modulates cardiomyocyte proliferation by regulating the hippo pathway

Heart ◽

10.1136/heartjnl-2017-311726.174 ◽

2017 ◽

Vol 103 (Suppl 5) ◽

pp. A122.2-A122 ◽

Cited By ~ 2

Author(s):

Dowan Kwon ◽

Yulia Kohar ◽

Nicholas Stafford ◽

Delvac Oceandy

Keyword(s):

Serotonin Receptor ◽

Hippo Pathway ◽

Cardiomyocyte Proliferation ◽

Serotonin Receptor 2B ◽

The Hippo Pathway

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Transcription of the Human 5-Hydroxytryptamine Receptor 2B (HTR2B) Gene Is under the Regulatory Influence of the Transcription Factors NFI and RUNX1 in Human Uveal Melanoma

International Journal of Molecular Sciences ◽

10.3390/ijms19103272 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3272 ◽

Cited By ~ 4

Author(s):

Manel Benhassine ◽

Sylvain Guérin

Keyword(s):

Transcription Factors ◽

Uveal Melanoma ◽

Serotonin Receptor ◽

Molecular Mechanisms ◽

Regulatory Region ◽

Gene Signature ◽

Regulatory Elements ◽

Gene Encoding ◽

Aberrant Expression ◽

Factor I

Because it accounts for 70% of all eye cancers, uveal melanoma (UM) is therefore the most common primary ocular malignancy. In this study, we investigated the molecular mechanisms leading to the aberrant expression of the gene encoding the serotonin receptor 2B (HTR2B), one of the most discriminating among the candidates from the class II gene signature, in metastatic and non-metastatic UM cell lines. Transfection analyses revealed that the upstream regulatory region of the HTR2B gene contains a combination of alternative positive and negative regulatory elements functional in HTR2B− but not in HTR23B+ UM cells. We demonstrated that both the transcription factors nuclear factor I (NFI) and Runt-related transcription factor I (RUNX1) interact with regulatory elements from the HTR2B gene to either activate (NFI) or repress (RUNX1) HTR2B expression in UM cells. The results of this study will help understand better the molecular mechanisms accounting for the abnormal expression of the HTR2B gene in uveal melanoma.

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Genotype-Dependent Sensitivity of Uveal Melanoma Cell Lines to Inhibition of B-Raf, MEK, and Akt Kinases: Rationale for Personalized Therapy

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.11-7398 ◽

2011 ◽

Vol 52 (10) ◽

pp. 7248 ◽

Cited By ~ 32

Author(s):

Nicholas Mitsiades ◽

Sue Anne Chew ◽

Bin He ◽

Aline I. Riechardt ◽

Theano Karadedou ◽

...

Keyword(s):

Cell Lines ◽

Uveal Melanoma ◽

Melanoma Cell ◽

Personalized Therapy ◽

Uveal Melanoma Cell ◽

Melanoma Cell Lines

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High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells

Cancers ◽

10.3390/cancers12102950 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2950

Author(s):

Kayleigh Slater ◽

Aisling B. Heeran ◽

Sandra Garcia-Mulero ◽

Helen Kalirai ◽

Rebeca Sanz-Pamplona ◽

...

Keyword(s):

Overall Survival ◽

Cell Lines ◽

Uveal Melanoma ◽

Therapeutic Potential ◽

Unmet Need ◽

Digital Pathology ◽

Disease Free Survival ◽

High Expression ◽

Poor Overall Survival ◽

Cysteinyl Leukotriene

Metastatic uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. There are no standard-of-care therapies available for the treatment of metastatic UM, hence it is a clinical area of urgent unmet need. Here, the clinical relevance and therapeutic potential of cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM was evaluated. High expression of CYSLTR1 or CYSLTR2 transcripts is significantly associated with poor disease-free survival and poor overall survival in UM patients. Digital pathology analysis identified that high expression of CysLT1 in primary UM is associated with reduced disease-specific survival (p = 0.012; HR 2.76; 95% CI 1.21–6.3) and overall survival (p = 0.011; HR 1.46; 95% CI 0.67–3.17). High CysLT1 expression shows a statistically significant (p = 0.041) correlation with ciliary body involvement, a poor prognostic indicator in UM. Small molecule drugs targeting CysLT1 were vastly superior at exerting anti-cancer phenotypes in UM cell lines and zebrafish xenografts than drugs targeting CysLT2. Quininib, a selective CysLT1 antagonist, significantly inhibits survival (p < 0.0001), long-term proliferation (p < 0.0001), and oxidative phosphorylation (p < 0.001), but not glycolysis, in primary and metastatic UM cell lines. Quininib exerts opposing effects on the secretion of inflammatory markers in primary versus metastatic UM cell lines. Quininib significantly downregulated IL-2 and IL-6 in Mel285 cells (p < 0.05) but significantly upregulated IL-10, IL-1β, IL-2 (p < 0.0001), IL-13, IL-8 (p < 0.001), IL-12p70 and IL-6 (p < 0.05) in OMM2.5 cells. Finally, quininib significantly inhibits tumour growth in orthotopic zebrafish xenograft models of UM. These preclinical data suggest that antagonism of CysLT1, but not CysLT2, may be of therapeutic interest in the treatment of UM.

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