The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

Pedersen, Stine Falsig; Flinck, Mette; Pardo, Luis A.

doi:10.3390/ijms22105209

Cited by 18 publications

(17 citation statements)

References 227 publications

(315 reference statements)

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“…Subplasmalemmal mitochondria buffer Ca 2+ movements during T cell activation [34], and ER-contacting mitochondria participate in Ca 2+ movements and lipid transfer [35]. Evidence indicates that a reciprocal relationship between dysregulated ion transport and mitochondria architecture may contribute to some cancers [36]. On the other hand, mito-nuclear communication has emerged as a new field of research to ascertain different crosstalk mechanisms between these organelles [37].…”

Section: Discussionmentioning

confidence: 99%

Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression

Capera

Pérez-Verdaguer

Navarro-Pérez

et al. 2021

Cancers

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The voltage-gated potassium channel Kv1.3 is a potential therapeutic target for obesity and diabetes. The genetic ablation and pharmacological inhibition of Kv1.3 lead to a lean phenotype in rodents. The mechanism of regulation of body weight and energy homeostasis involves Kv1.3 expression in different organs, including white and brown adipose tissues. Here, we show that Kv1.3 promotes the proliferation of preadipocytes through the control of mitochondrial dynamics. Kv1.3 is expressed in mitochondria exhibiting high affinity for the perinuclear population. The mitochondrial network is highly dynamic during the cell cycle, showing continuous fusion-fission events. The formation of a hyperfused mitochondrial network at the G1/S phase of the cell cycle is dependent on Kv1.3 expression. Our results demonstrate that Kv1.3 promotes preadipocyte proliferation and differentiation by controlling mitochondrial membrane potential and mitochondrial dynamics at the G1 phase of the cell cycle.

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Section: Discussionmentioning

confidence: 99%

Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression

Capera

Pérez-Verdaguer

Navarro-Pérez

et al. 2021

Cancers

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“…30 Finally, some studies have confirmed that there are extensive changes in ion homeostasis and membrane potential during the development of cancer, which play a key role in the occurrence and development of malignant tumors. 31 The above evidence reveals that FHIT and neighboring genes might impact the occurrence and progression of LUAD and LUSC.…”

Section: Discussionmentioning

confidence: 90%

System analysis of FHIT in LUAD and LUSC: The expression, prognosis, gene regulation network, and regulation targets

et al. 2022

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Background Fragile histidine triad ( FHIT) is a strong tumor suppressor gene, and cells deficient in FHIT are prone to acquiring cancer-promoting mutations. Due to its location, deletions within FHIT are common in cancer. Over 50% of cancers show loss of FHIT expression. However, to date, expression levels, gene regulatory networks, prognostic value, and target prediction of FHIT in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) have not been fully reported. Therefore, systematic analysis of FHIT expression, gene regulatory network, prognostic value, and targeted prediction in patients with LUAD and LUSC has important guiding significance, providing new therapeutic targets and strategies for clinical treatment of lung cancer to further improve the therapeutic effect of lung cancer. Methods Multiple free online databases were used for the abovementioned analysis in this study, including cBioPortal, TRRUST, Human Protein Atlas, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. Results FHIT was upregulated in patients with LUAD, and downregulated in patients with LUSC. Genetic alterations of FHIT were found in patients with LUAD (7%), and LUSC (10%). The promoter methylation of FHIT was lower in patients with LUAD and LUSC. FHIT expression significantly correlated with LUSC pathological stages. Furthermore, patients with LUAD and LUSC having low FHIT expression levels had a longer survival than those having high FHIT expression levels. FHIT and its neighboring genes (the 50 most frequently altered neighboring genes of FHIT) functioned in the regulation of protein kinase and DNA binding in patients with LUAD, as well as cell channels and membrane potential in patients with LUSC. Gene ontology enrichment analysis revealed that the functions of FHIT and its neighboring genes are mainly related to disordered domain-specific binding, protein kinase binding, and ion gated channel activity in patients with LUAD, as well as calcium ion binding and intracellular ligand-gated ion channel activity in patients with LUSC. Transcription factor targets of FHIT and its neighboring genes in patients with lung cancer were found: USF1, SOX6, USF2, SIRT1, VHL, LEF1, EZH2, TP53, HDAC1, ESR1, EGR1, YY1, MYC, RELA, NFKB1, and E2F1 in LUAD; and HDAC1, DNMT1, and E2F1 in LUSC. We further explored the FHIT-associated kinase (PRKCQ, AURKB and ATM in LUAD as well as PLK3 in LUSC) and FHIT-associated miRNA targets (MIR-188, MIR-323, and MIR-518A-2 in LUAD). Furthermore, the following genes had the strongest correlation with FHIT expression in patients with lung cancer: NICN1, HEMK1, and BDH2 in LUAD , and ZMAT1, TTC21A, and NICN1 in LUSC. FHIT expression was positively associated with immune cell infiltration (B cell) in patients with LUAD, as well as B cell, CD8 + T, CD4 + T cells, macrophages, and dendritic cells in patients with LUSC. Nevertheless, FHIT expression was negatively associated with CD8 + T cells and neutrophils in patients with LUAD. Conclusions The expression, gene regulatory network, prognostic value and targeted prediction of FHIT in patients with LUAD and LUSC were systematically analyzed and revealed in this study, thereby laying a foundation for further research on the role of FHIT in LUAD and LUSC occurrence. This study provides new LUAD and LUSC therapeutic targets and prognostic biomarkers as a reference for fundamental and clinical research.

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“…Mitochondria-targeted derivatives of TRAM-34 allow us to distinguish the pathophysiological roles of mitoK Ca 3.1 in cancer cells from those of the plasma membrane-located channel [ 81 ], since mitochondriotropic drugs reach the organelle within a few minutes [ 82 ]. We found that in contrast to the membrane-impermeant K Ca 3.1 inhibitor Maurotoxin [ 50 ], mitoTRAM-34 directly affected mitochondrial parameters such as membrane potential, ROS production, respiration, and morphology.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological targeting of the mitochondrial calcium-dependent potassium channel KCa3.1 triggers cell death and reduces tumor growth and metastasis in vivo

et al. 2022

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Ion channels are non-conventional, druggable oncological targets. The intermediate-conductance calcium-dependent potassium channel (KCa3.1) is highly expressed in the plasma membrane and in the inner mitochondrial membrane (mitoKCa3.1) of various cancer cell lines. The role mitoKCa3.1 plays in cancer cells is still undefined. Here we report the synthesis and characterization of two mitochondria-targeted novel derivatives of a high-affinity KCa3.1 antagonist, TRAM-34, which retain the ability to block channel activity. The effects of these drugs were tested in melanoma, pancreatic ductal adenocarcinoma and breast cancer lines, as well as in vivo in two orthotopic models. We show that the mitochondria-targeted TRAM-34 derivatives induce release of mitochondrial reactive oxygen species, rapid depolarization of the mitochondrial membrane, fragmentation of the mitochondrial network. They trigger cancer cell death with an EC50 in the µM range, depending on channel expression. In contrast, inhibition of the plasma membrane KCa3.1 by membrane-impermeant Maurotoxin is without effect, indicating a specific role of mitoKCa3.1 in determining cell fate. At sub-lethal concentrations, pharmacological targeting of mitoKCa3.1 significantly reduced cancer cell migration by enhancing production of mitochondrial reactive oxygen species and nuclear factor-κB (NF-κB) activation, and by downregulating expression of Bcl-2 Nineteen kD-Interacting Protein (BNIP-3) and of Rho GTPase CDC-42. This signaling cascade finally leads to cytoskeletal reorganization and impaired migration. Overexpression of BNIP-3 or pharmacological modulation of NF-κB and CDC-42 prevented the migration-reducing effect of mitoTRAM-34. In orthotopic models of melanoma and pancreatic ductal adenocarcinoma, the tumors at sacrifice were 60% smaller in treated versus untreated animals. Metastasis of melanoma cells to lymph nodes was also drastically reduced. No signs of toxicity were observed. In summary, our results identify mitochondrial KCa3.1 as an unexpected player in cancer cell migration and show that its pharmacological targeting is efficient against both tumor growth and metastatic spread in vivo.

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The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

Cited by 18 publications

References 227 publications

Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression

Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression

System analysis of FHIT in LUAD and LUSC: The expression, prognosis, gene regulation network, and regulation targets

Pharmacological targeting of the mitochondrial calcium-dependent potassium channel KCa3.1 triggers cell death and reduces tumor growth and metastasis in vivo

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