Cytochrome C Oxidase Subunit 4 (COX4): A Potential Therapeutic Target for the Treatment of Medullary Thyroid Cancer

Bikas, Athanasios; Jensen, Kirk; Patel, Aneeta; Costello, John; Reynolds, Sarah M; Mendonca-Torres, Maria Cecilia; Thakur, Shilpa; Kłubo-Gwieździńska, Joanna; Ylli, Dorina; Wartofsky, Léonard; Burman, Kenneth D.; Vasko, Vasyl

doi:10.3390/cancers12092548

Cited by 20 publications

(15 citation statements)

References 31 publications

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“…To investigate the downstream response of mitochondria to butyrate-mediated PGC1α signaling activation in NSC34-G93A cells, we examined both the mRNA and protein expression levels of the key molecules MTCO1, MTCO2, and COX4, which are critical for mitochondrial electron transportation [ 67 , 68 , 69 ]. One day after the transfection, the NSC34-G93A cells were incubated with 1 mM butyrate in the culture medium.…”

Section: Resultsmentioning

confidence: 99%

Butyrate Ameliorates Mitochondrial Respiratory Capacity of The Motor-Neuron-like Cell Line NSC34-G93A, a Cellular Model for ALS

et al. 2022

Biomolecules

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Mitochondrial defects in motor neurons are pathological hallmarks of ALS, a neuromuscular disease with no effective treatment. Studies have shown that butyrate, a natural gut-bacteria product, alleviates the disease progression of ALS mice overexpressing a human ALS-associated mutation, hSOD1G93A. In the current study, we examined the potential molecular mechanisms underlying the effect of butyrate on mitochondrial function in cultured motor-neuron-like NSC34 with overexpression of hSOD1G93A (NSC34-G93A). The live cell confocal imaging study demonstrated that 1mM butyrate in the culture medium improved the mitochondrial network with reduced fragmentation in NSC34-G93A cells. Seahorse analysis revealed that NSC34-G93A cells treated with butyrate showed an increase of ~5-fold in mitochondrial Spare Respiratory Capacity with elevated Maximal Respiration. The time-dependent changes in the mRNA level of PGC1α, a master regulator of mitochondrial biogenesis, revealed a burst induction with an early increase (~5-fold) at 4 h, a peak at 24 h (~19-fold), and maintenance at 48 h (8-fold) post-treatment. In line with the transcriptional induction of PGC1α, both the mRNA and protein levels of the key molecules (MTCO1, MTCO2, and COX4) related to the mitochondrial electron transport chain were increased following the butyrate treatment. Our data indicate that activation of the PGC1α signaling axis could be one of the molecular mechanisms underlying the beneficial effects of butyrate treatment in improving mitochondrial bioenergetics in NSC34-G93A cells.

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Section: Resultsmentioning

confidence: 99%

Butyrate Ameliorates Mitochondrial Respiratory Capacity of The Motor-Neuron-like Cell Line NSC34-G93A, a Cellular Model for ALS

et al. 2022

Biomolecules

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“…COX4I1 is a nuclear gene that encodes the common isoform of cytochrome c oxidase (COX) subunit 4 (COX 4-1), which is an integral regulatory part of the mitochondrial respiratory chain (31). COX4 was a biomarker for breast cancer (32) and medullary thyroid cancer (33). IKKBK, a key molecule in signaling to the transcription factor NFkB (34), is a very important regulator in tumorigenesis (35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Alternative mRNA Splicing in Adrenocortical Carcinoma

Liang

Sun

2021

Front. Endocrinol.

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BackgroundThis paper aims to identify alternative RNA splicing landscape and its prognostic value in adrenocortical carcinoma.MethodsThe alternative splicing events data with corresponding clinical information data of 79 ACC patients were obtained from the Cancer Genome Atlas and SpliceSeq package. Prognosis-associated AS events by using univariate Cox regression analysis were selected. Gene functional enrichment analysis demonstrated the potential pathways enriched by survival-associated AS. Prognosis-related splicing events were submitted to develop moderate predictors using Lasso regression model.ResultsOne thousand five survival-associated alternative splicing events were identified. The prognostic genes included ATXN2L, MEIS1, IKBKB, COX4I1. Functional enrichment analysis suggested that prognostic splicing events are associated with Wnt signaling pathway. A prediction model including 12 alternative splicing events was constructed by Lasso regression using train set. ROC analysis showed good performance of the prediction model in test set. Then, a nomogram integrating the clinical-pathological factors and riskscore was constructed for predicting 1‐ and 3‐year survival rate.ConclusionOur data provide a comprehensive bioinformatics analysis of AS events in ACC, providing biomarkers for disease progression and a potentially rich source of novel therapeutic targets.

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“…This correlates with the prognostic value of ATOX1 which was found to possess similar properties in the breast cancer. Another COX nuclear-encoded subunit, COX4, is also shown to be a valuable prognostic and therapeutic marker for medullary thyroid cancer treatment [ 34 ]. The role of the COX protein in cancer development and progression as well as its influence on altered signaling and metabolic pathways needs to be further explored.…”

Section: Copper Regulation In Cancermentioning

confidence: 99%

Recent Advances in Copper-Based Organic Complexes and Nanoparticles for Tumor Theranostics

Tsymbal

Agadzhanian

et al. 2022

Molecules

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Treatment of drug-resistant forms of cancer requires consideration of their hallmark features, such as abnormal cell death mechanisms or mutations in drug-responding molecular pathways. Malignant cells differ from their normal counterparts in numerous aspects, including copper metabolism. Intracellular copper levels are elevated in various cancer types, and this phenomenon could be employed for the development of novel oncotherapeutic approaches. Copper maintains the cell oxidation levels, regulates the protein activity and metabolism, and is involved in inflammation. Various copper-based compounds, such as nanoparticles or metal-based organic complexes, show specific activity against cancer cells according to preclinical studies. Herein, we summarize the major principles of copper metabolism in cancer cells and its potential in cancer theranostics.

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Cytochrome C Oxidase Subunit 4 (COX4): A Potential Therapeutic Target for the Treatment of Medullary Thyroid Cancer

Cited by 20 publications

References 31 publications

Butyrate Ameliorates Mitochondrial Respiratory Capacity of The Motor-Neuron-like Cell Line NSC34-G93A, a Cellular Model for ALS

Butyrate Ameliorates Mitochondrial Respiratory Capacity of The Motor-Neuron-like Cell Line NSC34-G93A, a Cellular Model for ALS

Prognostic Alternative mRNA Splicing in Adrenocortical Carcinoma

Recent Advances in Copper-Based Organic Complexes and Nanoparticles for Tumor Theranostics

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