Induction of apoptosis by intracellular potassium ion depletion: Using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells

Andersson, Britta; Janson, Veronica; Behnam‐Motlagh, Parviz; Henriksson, Roger; Grankvist, Kjell

doi:10.1016/j.tiv.2005.12.013

Cited by 42 publications

(40 citation statements)

References 12 publications

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“…Several miRNA have been shown to play a role in this process. In addition to the miR-155/miR-143/HK-II signaling pathway previously described (44), miR-21, a widely expressed hypoxamir known to be up-regulated in a variety of cancers (3,67), as well as in tissue ischemia (61), pulmonary hypertension (93), and cardiac fibrosis (79), has been shown to up-regulate Akt through suppression of its negative regulator phosphate and tensin homolog (81). The resulting inhibition of VDAC reduces ion flux between the mitochondria and the cytosol, resulting in mitochondrial hyperpolarization and an increased threshold for the opening of the MPTP.…”

Section: Targeting Mitochondrial Apoptosis Via the Akt/hk-ii Signalinmentioning

confidence: 99%

Hypoxamirs and Mitochondrial Metabolism

Cottrill

Chan²,

Loscalzo³

2014

Antioxidants & Redox Signaling

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Significance: Chronic hypoxia can drive maladaptive responses in numerous organ systems, leading to a multitude of chronic mammalian diseases. Oxygen homeostasis is intimately linked with mitochondrial metabolism, and dysfunction in these systems can combine to form the backbone of hypoxic-ischemic injury in multiple tissue beds. Increased appreciation of the crucial roles of hypoxia-associated miRNA (hypoxamirs) in metabolism adds a new dimension to our understanding of the regulation of hypoxia-induced disease. Recent Advances: Myriad factors related to glycolysis (e.g., aldolase A and hexokinase II), tricarboxylic acid cycle function (e.g., glutaminase and iron-sulfur cluster assembly protein 1/2), and apoptosis (e.g., p53) have been recently implicated as targets of hypoxamirs. In addition, several hypoxamirs have been implicated in the regulation of the master transcription factor of hypoxia, hypoxia-inducible factor-1a, clarifying how the cellular program of hypoxia is sustained and resolved. Critical Issues: Central to the discussion of metabolic change in hypoxia is the Warburg effect, a shift toward anaerobic metabolism that persists after normal oxygen levels have been restored. Many newly discovered targets of hypoxia-driven microRNA converge on pathways known to be involved in this pathological phenomenon and the apoptosis-resistant phenotype associated with it. Future Directions: The often synergistic functions of miRNA may make them ideal therapeutic targets. The use of antisense inhibitors is currently being considered in diseases in which hypoxia and metabolic dysregulation predominate. In addition, exploration of pleiotripic miRNA functions will likely continue to offer unique insights into the mechanistic relationships of their downstream target pathways and associated hypoxic phenotypes. Antioxid. Redox Signal. 21, 1189-1201.

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Section: Targeting Mitochondrial Apoptosis Via the Akt/hk-ii Signalinmentioning

confidence: 99%

Hypoxamirs and Mitochondrial Metabolism

Cottrill

Chan²,

Loscalzo³

2014

Antioxidants & Redox Signaling

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“…At least 90 % of the K + transport across the cell membrane is carried out by Na + ,K + , ATPase pump and NKCC1 activity [15,16]. Pharmacological modulation of K + transport not only changes P31 sensitivity to apoptosis inducers, but also induces apoptosis per se [15,[17][18][19]. Efflux of K + is necessary for cell shrinkage, and a reduced intracellular K + concentration is necessary for caspase activation [20].…”

Section: Introductionmentioning

confidence: 99%

Acquisition of Cisplatin-resistance in Malignant Mesothelioma Cells Abrogates Na+,K+,2Cl-;-cotransport Activity and Cisplatin-induced Early Membrane Blebbing

Janson

Andersson

Behnam‐Motlagh

et al. 2008

Cell Physiol Biochem

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Aims: Resistance mechanisms are important limiting factors in the treatment of solid malignancies with cis-diamminedichloroplatinum(II) (cisplatin). To gain further understanding of the effects of acquired cisplatin-resistance, we compared a human malignant pleural mesothelioma cell line (P31) to a sub-line (P31res1.2) with acquired cisplatin-resistance. Methods and Results: The role of Na⁺,K⁺,2Cl^--cotransport (NKCC1) activity in cisplatin-induced morphological changes and acquired cisplatin-resistance was investigated in a time-resolved manner. Acquisition of cisplatin-resistance resulted in markedly reduced NKCC1 activity, absence of cisplatin-induced early membrane blebbing, and increased basal caspase-3 activity. At equitoxic cisplatin concentrations, P31res1.2 cells had a faster activation of caspase-3 than P31 cells, but the end-stage cytotoxicity and number of cells with DNA fragmentation was similar. Bumetanide inhibition of NKCC1 activity in P31 cells repressed cisplatin-induced early-phase membrane blebbing but did not increase P31 cell resistance to cisplatin. Conclusions: Together, these results suggest that active NKCC1 was necessary for cisplatin-induced early membrane blebbing of P31 cells, but not for cisplatin-resistance. Thus, acquisition of cisplatin-resistance can affect mechanisms that have profound effects on cisplatin-induced morphological changes but are not necessary for the subsequent progression to apoptosis.

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“…Kv channels are redox-sensitive and activated by mitochondria-derived H 2 O 2 , a by-product of aerobic respiration (20). The inhibition or down-regulation of Kv channels suppresses apoptosis in multiple cell types, including tumor cells (22)(23)(24). Bonnet et al confirmed previous work (25) showing that DCA inhibits PDK and thus activates Kv1.5 channels (18).…”

mentioning

confidence: 99%

“…Kv1.5 in turn inhibits the Ca 2+ -dependent transcription factor NFAT (nuclear factor of activated T lymphocytes), which is known to impair both apoptosis and the expression of Kv1.5 in myocardial cells (26,27). DCA-mediated activation or up-regulation of Kv1.5 channels likely decreases cellular [K + ] i , thus activating caspases and triggering the demise of the cancer cells (21)(22)(23).…”

mentioning

confidence: 99%

Metabolic Targeting as an Anticancer Strategy: Dawn of a New Era?

2007

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As a result of a spectrum of mitochondrial defects, tumor cells often preferentially use glycolysis to generate adenosine triphosphate (ATP), even in the presence of oxygen, a phenomenon known as aerobic glycolysis, or the "Warburg effect." Dichloroacetate (DCA) is an inhibitor of mitochondrial pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), a gatekeeping enzyme for the entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle. In mice, DCA treatment appears to reactivate mitochondrial respiration in tumor cells, induces their selective killing, and suppresses cancer growth. These observations provide intriguing insights into the plasticity of tumor metabolism that may offer new opportunities for therapeutic intervention.

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Induction of apoptosis by intracellular potassium ion depletion: Using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells

Cited by 42 publications

References 12 publications

Hypoxamirs and Mitochondrial Metabolism

Hypoxamirs and Mitochondrial Metabolism

Acquisition of Cisplatin-resistance in Malignant Mesothelioma Cells Abrogates Na<sup>+</sup>,K<sup>+</sup>,2Cl<sup>-;</sup>-cotransport Activity and Cisplatin-induced Early Membrane Blebbing

Metabolic Targeting as an Anticancer Strategy: Dawn of a New Era?

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Induction of apoptosis by intracellular potassium ion depletion: Using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells

Cited by 42 publications

References 12 publications

Hypoxamirs and Mitochondrial Metabolism

Hypoxamirs and Mitochondrial Metabolism

Acquisition of Cisplatin-resistance in Malignant Mesothelioma Cells Abrogates Na<sup>&plus;</sup>,K<sup>&plus;</sup>,2Cl<sup>-;</sup>-cotransport Activity and Cisplatin-induced Early Membrane Blebbing

Metabolic Targeting as an Anticancer Strategy: Dawn of a New Era?

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Acquisition of Cisplatin-resistance in Malignant Mesothelioma Cells Abrogates Na<sup>+</sup>,K<sup>+</sup>,2Cl<sup>-;</sup>-cotransport Activity and Cisplatin-induced Early Membrane Blebbing