Metabolic Plasticity of Tumor Cell Mitochondria

Cannino, Giuseppe; Ciscato, Francesco; Masgras, Ionica; Sánchez-Martín, Carlos; Rasola, Andrea

doi:10.3389/fonc.2018.00333

Cited by 82 publications

(64 citation statements)

References 214 publications

(304 reference statements)

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“…Essential to metabolic plasticity is the regulation of mitochondria biogenesis. Mitochondria are the hubs that harbor the enzymes that drive the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, biosynthesis of nucleotides, amino acids and lipids, and calcium homeostasis (48). Mitochondrial biogenesis is mediated by a diverse signaling network.…”

Section: Regulators Of the Metabolic Phenotypes Associated With Breasmentioning

confidence: 99%

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

et al. 2019

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Within heterogeneous tumors, cancer stem cell (CSC) populations exhibit the greatest tumor initiation potential, promote metastasis, and contribute to therapy resistance. For breast cancer specifically, CSCs are identified by CD44 high CD24 low cell surface marker expression and increased aldehyde dehydrogenase activity. In general, bulk breast tumor cells possess altered energetics characterized by aerobic glycolysis. In contrast, breast CSCs appear to have adaptive metabolic plasticity that allows these tumor-initiating cells to switch between glycolysis and oxidative phosphorylation, depending on factors present in the tumor microenvironment (e.g., hypoxia, reactive oxygen species, availability of glucose). In this article, we review the regulatory molecules that may facilitate the metabolic plasticity of breast CSCs. These regulatory factors include epigenetic chromatin modifiers, non-coding RNAs, transcriptional repressors, transcription factors, energy and stress sensors, and metabolic enzymes. Furthermore, breast cancer cells acquire CSC-like characteristics and altered energetics by undergoing epithelial-mesenchymal transition (EMT). This energy costly process is paired with reprogrammed glucose metabolism by epigenetic modifiers that regulate expression of both EMT and other metabolism-regulating genes. The survival advantage imparted to breast CSCs by metabolic plasticity suggests that targeting the factors that mediate the energetic switch should hinder tumorigenesis and lead to improved patient outcomes.

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Section: Regulators Of the Metabolic Phenotypes Associated With Breasmentioning

confidence: 99%

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

et al. 2019

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“…The metabolic plasticity of cancer cells is known to favor acquired drug resistance and modulate prosurvival signaling pathways, allowing adaptation to changes in substrate availability [68][69][70]. GA-TPP + C 10 -induced mitochondrial dysfunction triggered early metabolic remodeling toward glycolysis, which may be mediated by AMPK signaling as previously described [29,71], and its inhibition with 2-DG promoted increased cell death in BC cells, similar to the reported synergistic effects of mitochondriatargeted antioxidants and vitamin E analogs and 2-DG in breast [72,73], hepatocellular [74] and pancreatic [75] carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells

Fuentes-Retamal

Sandoval-Acuña

Peredo-Silva

et al. 2020

Cells

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The mitochondrion has emerged as a promising therapeutic target for novel cancer treatments because of its essential role in tumorigenesis and resistance to chemotherapy. Previously, we described a natural compound, 10-((2,5-dihydroxybenzoyl)oxy)decyl) triphenylphosphonium bromide (GA-TPP+C10), with a hydroquinone scaffold that selectively targets the mitochondria of breast cancer (BC) cells by binding to the triphenylphosphonium group as a chemical chaperone; however, the mechanism of action remains unclear. In this work, we showed that GA-TPP+C10 causes time-dependent complex inhibition of the mitochondrial bioenergetics of BC cells, characterized by (1) an initial phase of mitochondrial uptake with an uncoupling effect of oxidative phosphorylation, as previously reported, (2) inhibition of Complex I-dependent respiration, and (3) a late phase of mitochondrial accumulation with inhibition of α-ketoglutarate dehydrogenase complex (αKGDHC) activity. These events led to cell cycle arrest in the G1 phase and cell death at 24 and 48 h of exposure, and the cells were rescued by the addition of the cell-penetrating metabolic intermediates l-aspartic acid β-methyl ester (mAsp) and dimethyl α-ketoglutarate (dm-KG). In addition, this unexpected blocking of mitochondrial function triggered metabolic remodeling toward glycolysis, AMPK activation, increased expression of proliferator-activated receptor gamma coactivator 1-alpha (pgc1α) and electron transport chain (ETC) component-related genes encoded by mitochondrial DNA and downregulation of the uncoupling proteins ucp3 and ucp4, suggesting an AMPK-dependent prosurvival adaptive response in cancer cells. Consistent with this finding, we showed that inhibition of mitochondrial translation with doxycycline, a broad-spectrum antibiotic that inhibits the 28 S subunit of the mitochondrial ribosome, in the presence of GA-TPP+C10 significantly reduces the mt-CO1 and VDAC protein levels and the FCCP-stimulated maximal electron flux and promotes selective and synergistic cytotoxic effects on BC cells at 24 h of treatment. Based on our results, we propose that this combined strategy based on blockage of the adaptive response induced by mitochondrial bioenergetic inhibition may have therapeutic relevance in BC.

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“…Mitochondria can promptly take up Ca 2+ released from ER, resulting in modulation of the activity of Krebs cycle enzymes and preventing deregulated increases in cytosolic [Ca 2+ ] (Cannino et al, 2018;Filadi et al, 2017). cl-HK2pep treatment rapidly boosts mitochondrial [Ca 2+ ] in a stable and Xe-Csensitive way (Movie 1 and Figure 2C-2E), rising mitochondrial [Ca 2+ ] to about 50 µM ( Fig 2F).…”

Section: Hk2 Detachment From Mams Elicits a Ca 2+ Flux Into Mitochondmentioning

confidence: 97%

Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca²⁺-dependent death of cancer cells

Rasola

Ciscato

Filadi

et al. 2019

Preprint

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Cancer cells undergo changes in metabolic and survival pathways that increase their malignancy.Isoform 2 of the glycolytic enzyme hexokinase (HK2) enhances both glucose metabolism and resistance to death stimuli in many neoplastic cell types. Here we observe that HK2 locates at mitochondria-endoplasmic reticulum (ER) contact sites called MAMs (Mitochondria-Associated Membranes). HK2 displacement from MAMs with a selective peptide triggers mitochondrial Ca 2+ overload caused by Ca 2+ release from ER via inositol-3-phosphate receptors (IP3Rs) and by Ca 2+ entry through plasma membrane. This results in Ca 2+ -dependent calpain activation, mitochondrial depolarization and cell death. The HK2-targeting peptide causes massive death of chronic lymphocytic leukemia B cells freshly isolated from patients, and an actionable form of the peptide reduces growth of breast and colon cancer cells allografted in mice without noxious effects on healthy tissues. These results identify a signalling pathway primed by HK2 displacement from MAMs that can be activated as anti-neoplastic strategy.

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Metabolic Plasticity of Tumor Cell Mitochondria

Cited by 82 publications

References 214 publications

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells

Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca²⁺-dependent death of cancer cells

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Metabolic Plasticity of Tumor Cell Mitochondria

Cited by 82 publications

References 214 publications

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells

Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca2+-dependent death of cancer cells

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Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca²⁺-dependent death of cancer cells