Metabolic and OXPHOS Activities Quantified by Temporal ex vivo Analysis Display Patient-Specific Metabolic Vulnerabilities in Human Breast Cancers

Koit, Andre; Timohhina, Natalja; Truu, Laura; Chekulayev, Vladimir; Gudlawar, Shivakumar; Shevchuk, Igor; Lepik, Katrin; Mallo, Léa; Kütner, Riina; Valvere, Vahur; Käämbre, Tuuli

doi:10.3389/fonc.2020.01053

Cited by 4 publications

(5 citation statements)

References 49 publications

(70 reference statements)

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“…Our recent studies revealed remarkable differences in the regulation of outer mitochondrial membrane (OMM) permeability between cultured tumor cells and clinical material from cancer patients (5,43). Comparative analysis of the biopsy or surgical cancer material and surrounding healthy tissue showed almost unchanged glycolytic activity and upregulation of OXPHOS in CRC, which is inconsistent with the data obtained by using cell culture (43)(44)(45)(46)(47). In addition, two widely used breast cancer cell lines MCF7 and MCF-MDA-231 failed to replicate mitochondrial function in respect to metabolic activity and OXPHOS as seen in respective human samples (43,46).…”

Section: Metabolic Reprogramming Of Colorectal Cancermentioning

confidence: 78%

“…Comparative analysis of the biopsy or surgical cancer material and surrounding healthy tissue showed almost unchanged glycolytic activity and upregulation of OXPHOS in CRC, which is inconsistent with the data obtained by using cell culture ( 43 – 47 ). In addition, two widely used breast cancer cell lines MCF7 and MCF-MDA-231 failed to replicate mitochondrial function in respect to metabolic activity and OXPHOS as seen in respective human samples ( 43 , 46 ).…”

Section: Metabolic Reprogramming Of Colorectal Cancermentioning

confidence: 99%

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Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis

et al. 2021

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Metabolic plasticity is the ability of the cell to adjust its metabolism to changes in environmental conditions. Increased metabolic plasticity is a defining characteristic of cancer cells, which gives them the advantage of survival and a higher proliferative capacity. Here we review some functional features of metabolic plasticity of colorectal cancer cells (CRC). Metabolic plasticity is characterized by changes in adenine nucleotide transport across the outer mitochondrial membrane. Voltage-dependent anion channel (VDAC) is the main protein involved in the transport of adenine nucleotides, and its regulation is impaired in CRC cells. Apparent affinity for ADP is a functional parameter that characterizes VDAC permeability and provides an integrated assessment of cell metabolic state. VDAC permeability can be adjusted via its interactions with other proteins, such as hexokinase and tubulin. Also, the redox conditions inside a cancer cell may alter VDAC function, resulting in enhanced metabolic plasticity. In addition, a cancer cell shows reprogrammed energy transfer circuits such as adenylate kinase (AK) and creatine kinase (CK) pathway. Knowledge of the mechanism of metabolic plasticity will improve our understanding of colorectal carcinogenesis.

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Section: Metabolic Reprogramming Of Colorectal Cancermentioning

confidence: 78%

Section: Metabolic Reprogramming Of Colorectal Cancermentioning

confidence: 99%

Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis

et al. 2021

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“…The best predictors for these states are determined by vimentin (VIM) and E-cadherin (CHD1) gene expression ratio combined with claudin 7 (CLDN7) expression using the TCGA breast cancer datasets ( 73 ) as well as the correlation of MMP2 expression to the progression of breast cancer to bone metastasis ( 74 ). Overexpression of the two mitochondrial proteins, citrate synthase (CS) and complex V subunit, ATP5C1 (or ATP5F1C), are described as markers for aggressiveness in triple negative breast cancer ( 75 , 76 ).…”

Section: Resultsmentioning

confidence: 99%

Role of mitochondrial translation in remodeling of energy metabolism in ER/PR(+) breast cancer

Koc

Koc²,

Kartal³

et al. 2022

Front. Oncol.

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Remodeling of mitochondrial energy metabolism is essential for the survival of tumor cells in limited nutrient availability and hypoxic conditions. Defects in oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis also cause a switch in energy metabolism from oxidative to aerobic glycolysis contributing to the tumor heterogeneity in cancer. Specifically, the aberrant expressions of mitochondrial translation components such as ribosomal proteins (MRPs) and translation factors have been increasingly associated with many different cancers including breast cancer. The mitochondrial translation is responsible for the synthesis 13 of mitochondrial-encoded OXPHOS subunits of complexes. In this study, we investigated the contribution of mitochondrial translation in the remodeling of oxidative energy metabolism through altered expression of OXPHOS subunits in 26 ER/PR(+) breast tumors. We observed a significant correlation between the changes in the expression of mitochondrial translation-related proteins and OXPHOS subunits in the majority of the ER/PR(+) breast tumors and breast cancer cell lines. The reduced expression of OXPHOS and mitochondrial translation components also correlated well with the changes in epithelial-mesenchymal transition (EMT) markers, E-cadherin (CHD1), and vimentin (VIM) in the ER/PR(+) tumor biopsies. Data mining analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) breast cancer proteome further supported the correlation between the reduced OXPHOS subunit expression and increased EMT and metastatic marker expression in the majority of the ER/PR(+) tumors. Therefore, understanding the role of MRPs in the remodeling of energy metabolism will be essential in the characterization of heterogeneity at the molecular level and serve as diagnostic and prognostic markers in breast cancer.

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“…DCA has been shown to induce higher toxicity to cells if they have defective mitochondria [ 34 , 35 ]. In fact, MCF7 cells have been proven to transform glutamate and also pyruvate into citrate at a lower rate than MDA-MB-231 breast cancer cells [ 70 ], and their expression of complex II, III, and V is also lower than other breast cancer cell lines [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

DR5 Up-Regulation Induced by Dichloroacetate Sensitizes Tumor Cells to Lipid Nanoparticles Decorated with TRAIL

Marco-Brualla

Miguel

Martínez-Lostao

et al. 2023

JCM

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Cancer resistance to treatments is a challenge that researchers constantly seek to overcome. For instance, TNF-related apoptosis-inducing ligand (TRAIL) is a potential good prospect as an anti-cancer therapy, as it attacks tumor cells but not normal cells. However, treatments based in soluble TRAIL provided incomplete clinical results and diverse formulations have been developed to improve its bioactivity. In previous works, we generated a new TRAIL formulation based in its attachment to the surface of unilamellar nanoliposomes (LUV-TRAIL). This formulation greatly increased apoptosis in a wide selection of tumor cell types, albeit a few of them remained resistant. On the other hand, it has been described that a metabolic shift in cancer cells can also alter its sensitivity to other treatments. In this work, we sought to increase the sensitivity of several tumor cell types resistant to LUV-TRAIL by previous exposure to the metabolic drug dichloroacetate (DCA), which forces oxidative phosphorylation. Results showed that DCA + LUV-TRAIL had a synergistic effect on both lung adenocarcinoma A549, colorectal HT29, and breast cancer MCF7 cells. Despite DCA inducing intracellular changes in a cell-type specific way, the increase in cell death by apoptosis was clearly correlated with an increase in death receptor 5 (DR5) surface expression in all cell lines. Therefore, DCA-induced metabolic shift emerges as a suitable option to overcome TRAIL resistance in cancer cells.

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Metabolic and OXPHOS Activities Quantified by Temporal ex vivo Analysis Display Patient-Specific Metabolic Vulnerabilities in Human Breast Cancers

Cited by 4 publications

References 49 publications

Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis

Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis

Role of mitochondrial translation in remodeling of energy metabolism in ER/PR(+) breast cancer

DR5 Up-Regulation Induced by Dichloroacetate Sensitizes Tumor Cells to Lipid Nanoparticles Decorated with TRAIL

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