Mitochondrial Metabolism in Melanoma

Huang, Chichi; Radi, Rakan; Arbiser, Jack L.

doi:10.3390/cells10113197

Cited by 18 publications

(8 citation statements)

References 181 publications

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“…Despite the differences observed between the two cell lines in terms of the number of proteins whose levels are modulated by GALC upregulation, categorization analysis indicates a significant enrichment in both cell lines of downmodulated proteins involved in mitochondrial functions, including oxidative phosphorylation, mitochondrial respiratory chain complexes, and aerobic respiration. Melanoma cells can shuttle between glycolysis and respiration depending upon conditions of growth, hypoxia, acidosis, and therapy, and BRAF activity has been shown to suppress oxidative phosphorylation, thus driving aerobic glycolysis in melanoma (see [ 45 ] and references therein). Thus, GALC appears to modulate the energetic plasticity of melanoma cells by metabolic reprogramming.…”

Section: Discussionmentioning

confidence: 99%

The Pro-Oncogenic Sphingolipid-Metabolizing Enzyme β-Galactosylceramidase Modulates the Proteomic Landscape in BRAF(V600E)-Mutated Human Melanoma Cells

Capoferri

Chiodelli

Corli

et al. 2023

IJMS

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β-Galactosylceramidase (GALC) is a lysosomal enzyme involved in sphingolipid metabolism by removing β-galactosyl moieties from β-galactosylceramide and β-galactosylsphingosine. Previous observations have shown that GALC may exert pro-oncogenic functions in melanoma and Galc silencing, leading to decreased oncogenic activity in murine B16 melanoma cells. The tumor-driving BRAF(V600E) mutation is present in approximately 50% of human melanomas and represents a major therapeutic target. However, such mutation is missing in melanoma B16 cells. Thus, to assess the impact of GALC in human melanoma in a more relevant BRAF-mutated background, we investigated the effect of GALC overexpression on the proteomic landscape of A2058 and A375 human melanoma cells harboring the BRAF(V600E) mutation. The results obtained by liquid chromatography-tandem mass spectrometry (LC-MS/MS) demonstrate that significant differences exist in the protein landscape expressed under identical cell culture conditions by A2058 and A375 human melanoma cells, both harboring the same BRAF(V600E)-activating mutation. GALC overexpression resulted in a stronger impact on the proteomic profile of A375 cells when compared to A2058 cells (261 upregulated and 184 downregulated proteins versus 36 and 14 proteins for the two cell types, respectively). Among them, 25 proteins appeared to be upregulated in both A2058-upGALC and A375-upGALC cells, whereas two proteins were significantly downregulated in both GALC-overexpressing cell types. These proteins appear to be involved in melanoma biology, tumor invasion and metastatic dissemination, tumor immune escape, mitochondrial antioxidant activity, endoplasmic reticulum stress responses, autophagy, and/or apoptosis. Notably, analysis of the expression of the corresponding genes in human skin cutaneous melanoma samples (TCGA, Firehose Legacy) using the cBioPortal for Cancer Genomics platform demonstrated a positive correlation between GALC expression and the expression levels of 14 out of the 27 genes investigated, thus supporting the proteomic findings. Overall, these data indicate for the first time that the expression of the lysosomal sphingolipid-metabolizing enzyme GALC may exert a pro-oncogenic impact on the proteomic landscape in BRAF-mutated human melanoma.

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Section: Discussionmentioning

confidence: 99%

The Pro-Oncogenic Sphingolipid-Metabolizing Enzyme β-Galactosylceramidase Modulates the Proteomic Landscape in BRAF(V600E)-Mutated Human Melanoma Cells

Capoferri

Chiodelli

Corli

et al. 2023

IJMS

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“…This combination therapy takes advantage of another mechanistic target of anti-tumor therapies: metabolism. The metabolic profiles of tumor cells influence their ability to activate the immune response and affect immune cell functions [ 47 , 100 , 101 , 102 , 103 , 104 , 105 ]. For example, tumor cells expressing the tryptophan-catabolizing enzyme IDO are known to lead to T-cell dysfunction [ 36 , 106 , 107 , 108 ].…”

Section: Novel Pro-immunogenic Adjuvant Therapiesmentioning

confidence: 99%

Enhancing Immunogenicity in Metastatic Melanoma: Adjuvant Therapies to Promote the Anti-Tumor Immune Response

Pelka

Guha

2023

Biomedicines

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Advanced melanoma is an aggressive form of skin cancer characterized by low survival rates. Less than 50% of advanced melanoma patients respond to current therapies, and of those patients that do respond, many present with tumor recurrence due to resistance. The immunosuppressive tumor-immune microenvironment (TIME) remains a major obstacle in melanoma therapy. Adjuvant treatment modalities that enhance anti-tumor immune cell function are associated with improved patient response. One potential mechanism to stimulate the anti-tumor immune response is by inducing immunogenic cell death (ICD) in tumors. ICD leads to the release of damage-associated molecular patterns within the TIME, subsequently promoting antigen presentation and anti-tumor immunity. This review summarizes relevant concepts and mechanisms underlying ICD and introduces the potential of non-ablative low-intensity focused ultrasound (LOFU) as an immune-priming therapy that can be combined with ICD-inducing focal ablative therapies to promote an anti-melanoma immune response.

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“…Overall, the interaction between the SOX family and metabolic modalities reflects the metabolic flexibility of melanoma ( 45 , 90 , 91 ). Glycolysis and mitochondrial respiration, the two major energy production pathways in tumor cells, are activated to varying extents based on genetic backgrounds, reflecting the metabolic heterogeneity of melanoma ( 73 , 92 – 94 ).…”

Section: Metabolic Heterogeneitymentioning

confidence: 99%

Metabolism heterogeneity in melanoma fuels deactivation of immunotherapy: Predict before protect

et al. 2022

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Malignant melanoma is widely acknowledged as the most lethal skin malignancy. The metabolic reprogramming in melanoma leads to alterations in glycolysis and oxidative phosphorylation (OXPHOS), forming a hypoxic, glucose-deficient and acidic tumor microenvironment which inhibits the function of immune cells, resulting in a low response rate to immunotherapy. Therefore, improving the tumor microenvironment by regulating the metabolism can be used to improve the efficacy of immunotherapy. However, the tumor microenvironment (TME) and the metabolism of malignant melanoma are highly heterogeneous. Therefore, understanding and predicting how melanoma regulates metabolism is important to improve the local immune microenvironment of the tumor, and metabolism regulators are expected to increase treatment efficacy in combination with immunotherapy. This article reviews the energy metabolism in melanoma and its regulation and prediction, the integration of immunotherapy and metabolism regulators, and provides a comprehensive overview of future research focal points in this field and their potential application in clinical treatment.

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Mitochondrial Metabolism in Melanoma

Cited by 18 publications

References 181 publications

The Pro-Oncogenic Sphingolipid-Metabolizing Enzyme β-Galactosylceramidase Modulates the Proteomic Landscape in BRAF(V600E)-Mutated Human Melanoma Cells

The Pro-Oncogenic Sphingolipid-Metabolizing Enzyme β-Galactosylceramidase Modulates the Proteomic Landscape in BRAF(V600E)-Mutated Human Melanoma Cells

Enhancing Immunogenicity in Metastatic Melanoma: Adjuvant Therapies to Promote the Anti-Tumor Immune Response

Metabolism heterogeneity in melanoma fuels deactivation of immunotherapy: Predict before protect

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