Microphthalmia-Associated Transcription Factor: A Differentiation Marker in Uveal Melanoma

Gelmi, Maria Chiara; Verdijk, Robert M.; Houtzagers, Laurien E.; Velden, Pieter A. van der; Kroes, Wilma G. M.; Luyten, Gregorius P M; Vu, T. H. Khanh; Jager, Martine J.

doi:10.3390/ijms24108861

Cited by 1 publication

(3 citation statements)

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“…MITF was suggested to have a dual role in benign and malignant melanocytic cells since it was proposed to promote local proliferation, while loss of MITF expression could increase invasion [ 97 , 98 ]. Gelmi et al [ 99 ] recently demonstrated that low MITF expression was associated with inflammatory markers and epithelial-mesenchymal transition. They proposed that MITF loss in UM could be related to de-differentiation to a less favorable epithelial-mesenchymal transition profile [ 99 ].…”

Section: Discussionmentioning

confidence: 99%

“…Gelmi et al [ 99 ] recently demonstrated that low MITF expression was associated with inflammatory markers and epithelial-mesenchymal transition. They proposed that MITF loss in UM could be related to de-differentiation to a less favorable epithelial-mesenchymal transition profile [ 99 ]. Borgdorff et al [ 100 ] found that AMPK was an important regulator for the maintenance of MITF protein levels in melanocytic cells.…”

Section: Discussionmentioning

confidence: 99%

“…It is an important regulator of melanogenesis and melanocyte development [97]. MITF was suggested to have a dual role in benign and malignant melanocytic cells since it was proposed to promote local proliferation, while loss of MITF expression could increase invasion [97,98]. Gelmi et al [99] recently demonstrated that low MITF expression was associated with inflammatory markers and epithelial-mesenchymal transition.…”

Section: Ampk Modulation Decreases Viability Of Um Cellsmentioning

confidence: 99%

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Modulation of AMPK Significantly Alters Uveal Melanoma Tumor Cell Viability

Deliktas,

Gedik,

Koc

et al. 2023

Ophthalmic Res

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Introduction: Uveal melanoma (UM) responds poorly to targeted therapies or immune checkpoint inhibitors. Adenosine monophosphate-activated protein kinase (AMPK) is a pivotal serine/threonine protein kinase that coordinates vital processes such as cell growth. Targeting AMPK pathway, which represents a critical mechanism mediating the survival of UM cells, may prove to be a novel treatment strategy for UM. We aimed to demonstrate the effects of AMPK modulation on UM cells. Methods: In silico analyses were performed to compare UM and normal melanocyte cells via Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA). The effects of AMPK modulation on cell viability and proliferation in UM cell lines with different molecular profiles (i.e., 92-1, MP46, OMM2.5, and Mel270) were investigated via XTT cell viability and proliferation assays after treating the cells with varying concentrations of A-769662 (AMPK activator) or dorsomorphin (AMPK inhibitor). Results: KEGG/GSEA studies demonstrated that genes implicated in the AMPK signaling pathway were differentially regulated in UM. Gene sets comprising genes involved in AMPK signaling and genes involved in energy-dependent regulation of mammalian target of rapamycin by liver kinase B1-AMPK were downregulated in UM. We observed gradual decreases in the numbers of viable UM cells as the concentration of A-769662 treatment increased. All UM cells demonstrated statistically significant decreases in cell viability when treated with 200 µ<sc>m</sc> A-769662. Moreover, the effects of AMPK inhibition on UM cells were potent, since low doses of dorsomorphin treatment resulted in significant decreases in viabilities of UM cells. The half maximal inhibitory concentration (IC50) values confirmed the potency of dorsomorphin treatment against UM in vitro. Conclusion: AMPK may act like a friend or a foe in cancer depending on the context. As such, the current study contributes to the literature in determining the effects of therapeutic strategies targeting AMPK in several UM cells. We propose a new perspective in the treatment of UM. Targeting AMPK pathway may open up new avenues in developing novel therapeutic approaches to improve overall survival in UM.

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Section: Discussionmentioning

confidence: 99%