Inhibition of Kv10.1 Channels Sensitizes Mitochondria of Cancer Cells to Antimetabolic Agents

Hernández‐Reséndiz, Ileana; Pacheu-Grau, David; Sánchez, Araceli; Pardo, Luis A.

doi:10.3390/cancers12040920

Cited by 15 publications

(14 citation statements)

References 54 publications

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“…In dopaminergic neurons treated with rotenone to induce mitochondrial fragmentation, block of K ATP channels diminished fragmentation, while activation of the channel increased it, although it is unclear whether this effect relies on the IMM channel population [ 30 ]. Plasma membrane K + channels have also been reported to influence mitochondrial dynamics, by still unclear mechanisms that could involve changes in Ca 2+ homeostasis [ 152 ].…”

Section: Mitochondrial Architecture Dynamics and Morphology In Normal Cellsmentioning

confidence: 99%

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

Pedersen

Flinck

Pardo

2021

IJMS

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Transport of ions and nutrients is a core mitochondrial function, without which there would be no mitochondrial metabolism and ATP production. Both ion homeostasis and mitochondrial phenotype undergo pervasive changes during cancer development, and both play key roles in driving the malignancy. However, the link between these events has been largely ignored. This review comprehensively summarizes and critically discusses the role of the reciprocal relationship between ion transport and mitochondria in crucial cellular functions, including metabolism, signaling, and cell fate decisions. We focus on Ca2+, H+, and K+, which play essential and highly interconnected roles in mitochondrial function and are profoundly dysregulated in cancer. We describe the transport and roles of these ions in normal mitochondria, summarize the changes occurring during cancer development, and discuss how they might impact tumorigenesis.

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Section: Mitochondrial Architecture Dynamics and Morphology In Normal Cellsmentioning

confidence: 99%

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

Pedersen

Flinck

Pardo

2021

IJMS

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“…At the clinical level, the evidence that K + channels are key actors in tumorigenesis is steadily piling up, and, consistently, the dysregulated expression of these channels is associated with a poor prognosis in a variety of human cancers [ 61 , 62 , 63 , 64 ]. The thorough interrogation conducted herein of human gene expression databases using CRC biopsies pinpointed KCNAB2, a regulatory subunit of a K + channel, as a suitable candidate to be a key player in the malignant transformation of colon tissue.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, different ion transport molecules, including K + channels, are already being studied as targets for cancer treatment [ 64 ]. Thus, the expression of Kv10.1, a K + channel encoded by the KCNH1 gene, is ectopically expressed in over 70% of solid human tumors and seems to participate in the regulation of key processes of tumorigenesis [ 61 ]. Importantly, the aberrant expression of Kv10.1 seems to originate from the altered expression of relevant regulators of cancer cell phenotypes, such as p53, E2F1, and miR-34a [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the expression of Kv10.1, a K + channel encoded by the KCNH1 gene, is ectopically expressed in over 70% of solid human tumors and seems to participate in the regulation of key processes of tumorigenesis [ 61 ]. Importantly, the aberrant expression of Kv10.1 seems to originate from the altered expression of relevant regulators of cancer cell phenotypes, such as p53, E2F1, and miR-34a [ 61 ]. According to a recent study, the inhibition of Kv10.1 expression or function leads to mitochondrial fragmentation, an increase in reactive oxygen species, and autophagy.…”

Section: Discussionmentioning

confidence: 99%

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A Drastic Shift in Lipid Adducts in Colon Cancer Detected by MALDI-IMS Exposes Alterations in Specific K+ Channels

Garate

Maimó-Barceló

Bestard-Escalas

et al. 2021

Cancers

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Even though colorectal cancer (CRC) is one of the most preventable cancers, it is one of the deadliest, and recent data show that the incidence in people <50 years has unexpectedly increased. While new techniques for CRC molecular classification are emerging, no molecular feature is as yet firmly associated with prognosis. Imaging mass spectrometry (IMS) lipidomic analyses have demonstrated the specificity of the lipid fingerprint in differentiating pathological from healthy tissues. During IMS lipidomic analysis, the formation of ionic adducts is common. Of particular interest is the [Na+]/[K+] adduct ratio, which already functions as a biomarker for homeostatic alterations. Herein, we show a drastic shift of the [Na+]/[K+] adduct ratio in adenomatous colon mucosa compared to healthy mucosa, suggesting a robust increase in K+ levels. Interrogating public databases, a strong association was found between poor diagnosis and voltage-gated potassium channel subunit beta-2 (KCNAB2) overexpression. We found this overexpression in three CRC molecular subtypes defined by the CRC Subtyping Consortium, making KCNAB2 an interesting pharmacological target. Consistently, its pharmacological inhibition resulted in a dramatic halt in commercial CRC cell proliferation. Identification of potential pharmacologic targets using lipid adduct information emphasizes the great potential of IMS lipidomic techniques in the clinical field.

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“…Thus, metabolic reprogramming can be further used to diagnose, monitor and treat cancer. In recent years, new metabolic inhibitors have been developed for the clinical treatment of cancer (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Prognostic Markers for Acute Myeloid Leukemia Based on Four Metabolic Genes

Zhang

Wang

et al. 2020

Front. Oncol.

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Background: Metabolic reprogramming is the core characteristic of tumors during the development of tumors, and cancer cells can rely on metabolic changes to support their rapid growth. Nevertheless, an overall analysis of metabolic markers in acute myeloid leukemia (AML) is absent and urgently needed. Methods: Within this work, genetic expression, mutation data and clinical data of AML were queried from Genotype-Tissue Expression (GTEx) database, The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. The tumor samples of TCGA were randomly divided into a training group (64 samples) and an internal validation group (64 samples) at one time, and the tumor samples of GEO served as two external validation groups (99 samples, 374 samples). According to the expression levels of survival-associated metabolic genes, we divided all TCGA tumor samples into high, medium and low metabolism groups, and evaluated the immune cell activity in the tumor microenvironment of the three metabolism groups by single-sample gene set enrichment analysis (ssGSEA) algorithm. Finally, we examined the mutations and prognostic effects of each model gene. Results: Four metabolism-related genes were screened and applied to construct a prognostic model for AML, giving excellent results. As for the area under the curve (AUC) value of receiver operating characteristic (ROC) curve, the training group was up to 0.902 (1-year), 0.81 (3-year), and 0.877 (5-year); and the internal and external validation groups also met the expected standards, showing high potency in predicting patient outcome. Univariate and multivariate prognostic analyses indicated that the riskScore obtained from our prognostic model was an independent prognostic factor. ssGSEA analysis revealed the high metabolism group had higher immune activity. Single and multiple gene survival analysis validated that each model gene had significant effects on the overall survival of AML patients. Conclusions: In our study, a high-efficiency prognostic prediction model was built and validated for AML patients. The results showed that metabolism-related genes could become potential prognostic biomarkers for AML.

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Inhibition of Kv10.1 Channels Sensitizes Mitochondria of Cancer Cells to Antimetabolic Agents

Cited by 15 publications

References 54 publications

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

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

A Drastic Shift in Lipid Adducts in Colon Cancer Detected by MALDI-IMS Exposes Alterations in Specific K+ Channels

Comprehensive Analysis of Prognostic Markers for Acute Myeloid Leukemia Based on Four Metabolic Genes

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