scholarly journals Vitamin D Enhances Anticancer Properties of Cediranib, a VEGFR Inhibitor, by Modulation of VEGFR2 Expression in Melanoma Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Anna Piotrowska ◽  
Fernando Pereira Beserra ◽  
Justyna Marta Wierzbicka ◽  
Joanna Irena Nowak ◽  
Michał Aleksander Żmijewski
Keyword(s):  
Vitamin D ◽  
Cell Proliferation ◽  
Malignant Melanoma ◽  
Melanoma Cell ◽  
Kinase Inhibitor ◽  
Melanoma Cells ◽  
New Combination ◽  
Mrna Levels ◽  
Human Malignant Melanoma ◽  
Melanoma Cell Proliferation

Regardless of the recent groundbreaking introduction of personalized therapy, melanoma continues to be one of the most lethal skin malignancies. Still, a substantial proportion of patients either fail to respond to the therapy or will relapse over time, representing a challenging clinical problem. Recently, we have shown that vitamin D enhances the effectiveness of classical chemotherapeutics in the human malignant melanoma A375 cell line. In search for new combination strategies and adjuvant settings to improve melanoma patient outcomes in the current study, the effects of cediranib (AZD2171), an oral tyrosine kinase inhibitor of VEGFR1-3, PDGFR, and c-KIT, used in combination either with 1,25(OH)2D3 or with low-calcemic analog calcipotriol were tested on four human malignant melanoma cell lines (A375, MNT-1, RPMI-7951, and SK-MEL-28). Melanoma cells were pretreated with vitamin D and subsequently exposed to cediranib. We observed a marked decrease in melanoma cell proliferation (A375 and SK-MEL-28), G2/M cell cycle arrest, and a significant decrease in melanoma cell mobility in experimental conditions used (A375). Surprisingly, concurrently with a very desirable decrease in melanoma cell proliferation and mobility, we noticed the upregulation of VEGFR2 at both protein and mRNA levels. No effect of vitamin D was observed in MNT-1 and RPMI-7951 melanoma cells. It seems that vitamin D derivatives enhance cediranib efficacy by modulation of VEGFR2 expression in melanoma cells expressing VEGFR2. In conclusion, our experiments demonstrated that vitamin D derivatives hold promise as novel adjuvant candidates to conquer melanoma, especially in patients suffering from vitamin D deficiency. However, further extensive research is indispensable to reliably assess their potential benefits for melanoma patients.

Involvement of hydrogen peroxide in histamine-induced modulation of WM35 human malignant melanoma cell proliferation

2009 ◽  
Vol 46 (11) ◽  
pp. 1510-1515 ◽  
Author(s):  
Vanina A. Medina ◽  
Noelia A. Massari ◽  
Graciela P. Cricco ◽  
Gabriela A. Martín ◽  
Rosa M. Bergoc ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Cell Proliferation ◽  
Malignant Melanoma ◽  
Melanoma Cell ◽  
Human Malignant Melanoma ◽  
Malignant Melanoma Cell ◽  
Melanoma Cell Proliferation

scholarly journals Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1369 ◽  
Author(s):  
Jana Jandova ◽  
Jessica Perer ◽  
Anh Hua ◽  
Jeremy A. Snell ◽  
Georg T. Wondrak
Keyword(s):  
Malignant Melanoma ◽  
Enzymatic Activity ◽  
Melanoma Cell ◽  
Melanoma Cells ◽  
Metabolic Reprogramming ◽  
Invasion And Metastasis ◽  
Genetic Rescue ◽  
Human Malignant Melanoma ◽  
Glyoxalase 1 ◽  
Molecular Determinant

Metabolic reprogramming is a molecular hallmark of cancer. Recently, we have reported the overexpression of glyoxalase 1 (encoded by GLO1), a glutathione-dependent enzyme involved in detoxification of the reactive glycolytic byproduct methylglyoxal, in human malignant melanoma cell culture models and clinical samples. However, the specific role of GLO1 in melanomagenesis remains largely unexplored. Here, using genetic target modulation, we report the identification of GLO1 as a novel molecular determinant of invasion and metastasis in malignant melanoma. First, A375 human malignant melanoma cells with GLO1 deletion (A375-GLO1_KO) were engineered using CRISPR/Cas9, and genetic rescue clones were generated by stable transfection of KO clones employing a CMV-driven GLO1 construct (A375-GLO1_R). After confirming GLO1 target modulation at the mRNA and protein levels (RT-qPCR, immunodetection, enzymatic activity), phenotypic characterization indicated that deletion of GLO1 does not impact proliferative capacity while causing significant sensitization to methylglyoxal-, chemotherapy-, and starvation-induced cytotoxic stress. Employing differential gene expression array analysis (A375-GLO1_KO versus A375-GLO1_WT), pronounced modulation of epithelial mesenchymal transition (EMT)-related genes [upregulated: CDH1, OCLN, IL1RN, PDGFRB, SNAI3; (downregulated): BMP1, CDH2, CTNNB1, FN1, FTH1, FZD7, MELTF, MMP2, MMP9, MYC, PTGS2, SNAI2, TFRC, TWIST1, VIM, WNT5A, ZEB1, and ZEB2 (up to tenfold; p < 0.05)] was observed—all of which are consistent with EMT suppression as a result of GLO1 deletion. Importantly, these expression changes were largely reversed upon genetic rescue employing A375-GLO1_R cells. Differential expression of MMP9 as a function of GLO1 status was further substantiated by enzymatic activity and ELISA analysis; phenotypic assessment revealed the pronounced attenuation of morphological potential, transwell migration, and matrigel 3D-invasion capacity displayed by A375-GLO1_KO cells, reversed again in genetic rescue clones. Strikingly, in a SCID mouse metastasis model, lung tumor burden imposed by A375-GLO1_KO cells was strongly attenuated as compared to A375-GLO1_WT cells. Taken together, these prototype data provide evidence in support of a novel function of GLO1 in melanoma cell invasiveness and metastasis, and ongoing investigations explore the function and therapeutic potential of GLO1 as a novel melanoma target.

scholarly journals Nuclear Localization of BRAFV600E Is Associated with HMOX-1 Upregulation and Aggressive Behavior of Melanoma Cells

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 311
Author(s):  
Mourad Zerfaoui ◽  
Eman Toraih ◽  
Emmanuelle Ruiz ◽  
Youssef Errami ◽  
Abdallah S. Attia ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nuclear Localization ◽  
Melanoma Cell ◽  
Braf Inhibitor ◽  
Melanoma Cells ◽  
Heme Oxygenase 1 ◽  
Biological Targets ◽  
Melanoma Cell Proliferation

Background: Previously, we have demonstrated that nuclear BRAFV600E is associated with melanoma aggressiveness and vemurafenib resistance. However, the underlying mechanisms of how nuclear localization of BRAFV600E promotes cell aggressiveness have not yet been investigated. Despite therapeutic advancements targeting cutaneous melanoma, unknown cellular processes prevent effective treatment for this malignancy, prompting an urgent need to identify new biological targets. This study aims to explore the association of inducible heme oxygenase 1 (HMOX-1) with nuclear BRAFV600E in promoting melanoma aggressiveness. Methods: Proteomics analysis was performed to identify the interacting partner(s) of nuclear BRAFV600E. Immunohistochemistry was applied to evaluate the levels of HMOX-1 and nuclear BRAFV600E expression in melanoma and adjacent healthy tissues. Immunofluorescence assessed the nuclear localization of BRAFV600E in vemurafenib-resistant A375R melanoma cells. Further study of HMOX-1 knockdown or BRAFV600E overexpression in melanoma cells suggested a role for HMOX-1 in the regulation of cell proliferation in vivo and in vitro. Finally, Western blot analysis was performed to confirm the pathway by which HMOX-1 mediates Akt signaling. Results: Proteomics results showed that HMOX-1 protein expression was 10-fold higher in resistant A375R cells compared to parental counterpart cells. In vitro and in vivo results illustrate that nuclear BRAFV600E promotes HMOX-1 overexpression, whereas HMOX-1 reduction represses melanoma cell proliferation and tumor growth. Mechanistic studies revealed that HMOX-1 was associated with nuclear BRAFV600E localization, thus promoting melanoma proliferation via a persistent activation of the AKT pathway. Conclusions: Our results highlight a previously unknown mechanism in which the nuclear BRAFV600E/HMOX-1/AKT axis plays an essential role in melanoma cell proliferation. Targeting HMOX-1 could be a novel method for treating melanoma patients who develop BRAF inhibitor resistance.

scholarly journals The α9 Nicotinic Acetylcholine Receptor Mediates Nicotine-Induced PD-L1 Expression and Regulates Melanoma Cell Proliferation and Migration

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1991 ◽  
Author(s):  
Hai Duong Nguyen ◽  
You-Cheng Liao ◽  
Yuan-Soon Ho ◽  
Li-Ching Chen ◽  
Hui-Wen Chang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Melanoma Cell ◽  
Melanoma Cells ◽  
Nicotinic Acetylcholine ◽  
Cell Proliferation And Migration ◽  
Melanoma Cell Proliferation ◽  
And Migration ◽  
Proliferation And Migration

Cigarette smoking is associated with an increased risk of melanoma metastasis. Smokers show higher PD-L1 expression and better responses to PD-1/PD-L1 inhibitors than nonsmokers. Here, we investigate whether nicotine, a primary constituent of tobacco, induces PD-L1 expression and promotes melanoma cell proliferation and migration, which is mediated by the α9 nicotinic acetylcholine receptor (α9-nAChR). α9-nAChR overexpression in melanoma using melanoma cell lines, human melanoma tissues, and assessment of publicly available databases. α9-nAChR expression was significantly correlated with PD-L1 expression, clinical stage, lymph node status, and overall survival (OS). Overexpressing or knocking down α9-nAChR in melanoma cells up- or downregulated PD-L1 expression, respectively, and affected melanoma cell proliferation and migration. Nicotine-induced α9-nAChR activity promoted melanoma cell proliferation through stimulation of the α9-nAChR-mediated AKT and ERK signaling pathways. In addition, nicotine-induced α9-nAchR activity promoted melanoma cell migration via activation of epithelial-mesenchymal transition (EMT). Moreover, PD-L1 expression was upregulated in melanoma cells after nicotine treatment via the transcription factor STAT3 binding to the PD-L1 promoter. These results highlight that nicotine-induced α9-nAChR activity promotes melanoma cell proliferation, migration, and PD-L1 upregulation. This study may reveal important insights into the mechanisms underlying nicotine-induced melanoma growth and metastasis through α9-nAChR-mediated carcinogenic signals and PD-L1 expression.

scholarly journals Mitochondrial Fatty Acid Oxidation Is Not Vital for Melanoma Cell Proliferation and Migration

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 314-314
Author(s):  
Marianne Collard ◽  
George Chen ◽  
Hyeon Jeong Lee ◽  
Zhicong Chen ◽  
Ji-Xen Cheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Fatty Acid ◽  
Melanoma Cell ◽  
Melanoma Cells ◽  
Acid Oxidation ◽  
Cell Proliferation And Migration ◽  
Excess Adiposity ◽  
Melanoma Cell Proliferation ◽  
And Migration ◽  
Proliferation And Migration

Abstract Objectives Melanoma, the 5th most common cancer in the US, is the most aggressive form of skin cancer. Excess adiposity is associated with an increased risk of melanoma in males, and a high-fat diet promotes melanoma tumor growth in mice. Our group found that lipid droplet (LD) content increases with melanoma cell aggressiveness and that fatty acid uptake inhibition reduces cell proliferation and migration; however, the function of these lipids in melanoma is unknown. Since lipids can be used to produce energy by fatty acid oxidation (FAO), we sought to determine whether melanoma cells were using FAO to maintain aggressiveness. Methods Gene expression microarray was used to identify differences in gene expression, which was confirmed by RT-qPCR. WM983A, WM983B, 1205Lu and A375 human melanoma cells were treated with 5 µM Etomoxir and cell proliferation, migration, and respiration were quantified using the Quant-iT™ PicoGreen™ dsDNA Assay Kit, Boyden Chamber transwell migration, and Seahorse XFe96 Flux Analyzer, respectively. Results The most significantly altered genes expressed between four invasive, lipid-rich and four non-invasive, lipid-poor melanoma cells pertained to fatty acid metabolism. Carnitine palmitoyltransferase 1A (CPT1a), the rate limiting enzyme in mitochondrial FAO (mFAO), mRNA was increased in lipid-rich cells compared to the lipid-poor cells (p &lt; 0.05, n = 6–7), indicating that melanoma cells may use LD lipids for mFAO. To determine the importance of mFAO to melanoma cells, we inhibited mFAO with etomoxir, an irreversible CPT1 inhibitor. Treatment of lipid-rich 1205Lu and A375 cells or lipid-poor WM983A and WM983B cells with etomoxir for 4 days had no effect on cell proliferation. Extracellular flux analysis of cells with or without etomoxir showed no difference in ATP production, indicating that melanoma cells do not use mFAO to generate energy under normal conditions. In motile cells, etomoxir reduced lipid-rich A375 cell migration by 8.8% (p = 0.05, n = 2). Conclusions Lipids play a role in melanoma aggressiveness; however, our results indicate that mFAO of lipids is not vital to melanoma cell proliferation or migration. Further studies are required to understand the implication of excess adiposity and circulating lipids in melanoma development and progression. Funding Sources Institutional Department Fund

scholarly journals LncRNA POU3F3 promotes melanoma cell proliferation by downregulating lncRNA MEG3

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yingnan Liu ◽  
Yongqing Zhuang ◽  
Xiaokuan Fu ◽  
Chaofei Li
Keyword(s):  
Cell Proliferation ◽  
Melanoma Cell ◽  
Inverse Correlation ◽  
Melanoma Cells ◽  
Sequencing Analysis ◽  
Tumor Tissues ◽  
Melanoma Cell Proliferation ◽  
Esophageal Squamous Cell Carcinomas ◽  
Melanoma Patients

Abstract Background LncRNA POU3F3 (POU3F3) is overexpressed and plays oncogenic roles in esophageal squamous-cell carcinomas. LncRNA MEG3 (MEG3) has been characterized as a tumor suppressive lncRNA in different types of cancer. Our preliminary deep sequencing analysis revealed the inverse correlation between POU3F3 and MEG2 across melanoma tissues, indicating the interaction between them in melanoma. Therefore, this study was performed to investigate the crosstalk between POU3F3 and MEG3 in melanoma. Methods Tumor and adjacent healthy tissues collected from 60 melanoma patients were subjected to RNA extractions and RT-qPCRs to analyze the differential expression of POU3F3 and MEG2 in melanoma. In melanoma cells, POU3F3 and MEG2 were overexpressed to study the interactions between them. CCK-8 assays were performed to analyze the roles of POU3F3 and MEG2 in regulating melanoma cell proliferation. Results We found that POU3F3 was upregulated, while lncRNA MEG3 was downregulated in melanoma. Expression levels of POU3F3 and MEG3 were inversely correlated across tumor tissues. In vitro experiments showed that POU3F3 overexpression decreased MEG3 expression in melanoma cells, while MEG3 overexpression failed to affect POU3F3. POU3F3 overexpression increased melanoma cell proliferation, while MEG3 overexpression decreased melanoma cell proliferation. In addition, rescue experiments showed that MEG3 overexpression attenuated the enhancing effects of POU3F3 overexpression. Conclusion POU3F3 may promote melanoma cell proliferation by downregulating MEG3.

scholarly journals FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation

2019 ◽  
Vol 117 (1) ◽  
pp. 584-594 ◽  
Author(s):  
Cheol-Jung Lee ◽  
Hyun-Jung An ◽  
Seung-Min Kim ◽  
Sun-Mi Yoo ◽  
Juhee Park ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Melanoma Cell ◽  
Essential Role ◽  
Inverse Correlation ◽  
Colony Growth ◽  
Melanoma Cells ◽  
Tissue Array ◽  
Cancer Tissue ◽  
Protein Levels ◽  
Melanoma Cell Proliferation

In this study, we provide critical evidence that STAT2 stability regulation plays an essential role in melanoma cell proliferation and colony growth. We found that the interaction of FBXW7 and STAT2 induced STAT2 destabilization via a ubiquitination-mediated proteasomal degradation pathway. Notably, GSK3β-mediated STAT2 phosphorylation facilitated STAT2–FBXW7 interactions via the DNA binding domain of STAT2 and domains 1, 2, 6, and 7 of FBXW7 WD40. Importantly, the inverse correlation between protein levels of STAT2 and FBXW7 were observed not only in human melanoma cells but also in a human skin cancer tissue array. The relationship between protein levels of STAT2 and FBXW7, cell proliferation, and colony growth were similarly observed in the melanoma cell lines SK-MEL-2, -5, and -28. Moreover, STAT2 knockdown in melanoma cells suppressed melanoma cell proliferation and colony formation. These data demonstrated that FBXW7-mediated STAT2 stability regulation plays an essential role in melanoma cell proliferation and cancer growth.

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