Cell cycle progression and apoptosis after irradiation in an acidic environment

Park, H J; Lyons, John C.; Ohtsubo, Toshio; Song, Chang W.

doi:10.1038/sj.cdd.4400702

Cited by 38 publications

(32 citation statements)

References 20 publications

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“…However, increased glycolysis caused by HIF-1␣ may not be beneficial for tumor cells which already exhibit elevated glycolysis due to other genetic mutations, since increased fermentation results in overproduction of lactic acid. Several reports indicate that p53 is only activated to promote apoptosis and cell cycle arrest in acidic environments (71,74,87,109). Furthermore, the hypoxia-inducible proapoptotic gene bNIP-3 is also only active in acidic environments (9,96).…”

Section: Discussionmentioning

confidence: 99%

“…Although HIF-2␣ does not regulate glycolytic genes, it does stimulate GLUT-1 expression in 786-O and HEK293 TET-on cells. Increased glucose transport into cells may provide a survival advantage, since glucose is required for Akt-mediated inhibition of cytochrome c release and apoptosis (30,74). Akt has been shown to be activated by hypoxia (1,8,16,31,48,76).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation

Wang

Chodosh

et al. 2003

Molecular and Cellular Biology

1,240

1,078

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Transcriptional responses to hypoxia are primarily mediated by hypoxia-inducible factor (HIF), a heterodimer of HIF-␣ and the aryl hydrocarbon receptor nuclear translocator subunits. The HIF-1␣ and HIF-2␣ subunits are structurally similar in their DNA binding and dimerization domains but differ in their transactivation domains, implying they may have unique target genes. Previous studies using Hif-1␣ ؊/؊ embryonic stem and mouse embryonic fibroblast cells show that loss of HIF-1␣ eliminates all oxygen-regulated transcriptional responses analyzed, suggesting that HIF-2␣ is dispensable for hypoxic gene regulation. In contrast, HIF-2␣ has been shown to regulate some hypoxia-inducible genes in transient transfection assays and during embryonic development in the lung and other tissues. To address this discrepancy, and to identify specific HIF-2␣ target genes, we used DNA microarray analysis to evaluate hypoxic gene induction in cells expressing HIF-2␣ but not HIF-1␣. In addition, we engineered HEK293 cells to express stabilized forms of HIF-1␣ or HIF-2␣ via a tetracycline-regulated promoter. In this first comparative study of HIF-1␣ and HIF-2␣ target genes, we demonstrate that HIF-2␣ does regulate a variety of broadly expressed hypoxia-inducible genes, suggesting that its function is not restricted, as initially thought, to endothelial cell-specific gene expression. Importantly, HIF-1␣ (and not HIF-2␣) stimulates glycolytic gene expression in both types of cells, clearly showing for the first time that HIF-1␣ and HIF-2␣ have unique targets.Oxygen (O 2 ), the final electron acceptor during oxidative phosphorylation, is absolutely required for invertebrate and vertebrate life. The immediate response to O 2 deprivation (hypoxia) is a defense phase, which suppresses ATP consumption by arresting protein translation and ion channel activity, two major ATP sinks during normoxia. During a rescue phase, in spite of a general reduction in RNA synthesis, transcription of some genes increases dramatically under low O 2 (21, 34). These hypoxia-responsive genes are involved in glucose transport, glycolysis, erythropoiesis, angiogenesis, vasodilation, and respiratory rate, and together they function to minimize the effects caused by low O 2 at cellular, tissue and systemic levels (93, 106).The activation of many O 2 -regulated genes is mediated by hypoxia-inducible factor (HIF), a heterodimer consisting of HIF-1␣ and HIF-1␤ (also called the aryl hydrocarbon receptor nuclear translocator [ARNT]) in most cells (52,104,105). Both HIF-1␣ and ARNT belong to the basic helix-loop-helix (bHLH)-Per-Arnt-Sim (PAS) family of transcription factors, which share several conserved structural domains, including a bHLH region for DNA binding and two PAS domains for target gene specificity and dimerization (102). Although ARNT is absolutely required for HIF activity (63, 110), HIF function is primarily regulated by HIF-1␣ protein stability (37,46,84). Under normoxia, HIF-1␣ is ubiquitinated through interaction with the von Hippel-Lindau tumor suppr...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation

Wang

Chodosh

et al. 2003

Molecular and Cellular Biology

1,240

1,078

View full text Add to dashboard Cite

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“…Both lactate acid and H 2 CO 3 production lead to excretion of protons and a decline in pH of the surrounding matrix. This tissue acidosis triggers a p53-mediated cell death of neighbouring healthy cells (Williams et al, 1999;Park et al, 2000). Tumour cells survive due to mutations in p53 or some other components in the apoptosis pathways.…”

Section: Discussionmentioning

confidence: 99%

Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted

et al. 2006

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Tumours ferment glucose to lactate even in the presence of oxygen (aerobic glycolysis; Warburg effect). The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis and glucose degradation to lactate. The nonoxidative part of the PPP is controlled by transketolase enzyme reactions. We have detected upregulation of a mutated transketolase transcript (TKTL1) in human malignancies, whereas transketolase (TKT) and transketolase-like-2 (TKTL2) transcripts were not upregulated. Strong TKTL1 protein expression was correlated to invasive colon and urothelial tumours and to poor patients outcome. TKTL1 encodes a transketolase with unusual enzymatic properties, which are likely to be caused by the internal deletion of conserved residues. We propose that TKTL1 upregulation in tumours leads to enhanced, oxygen-independent glucose usage and a lactatebased matrix degradation. As inhibition of transketolase enzyme reactions suppresses tumour growth and metastasis, TKTL1 could be the relevant target for novel anti-transketolase cancer therapies. We suggest an individualised cancer therapy based on the determination of metabolic changes in tumours that might enable the targeted inhibition of invasion and metastasis.

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“…The changes in cyclin B1-Cdc2 kinase activity in the cells irradiated and treated with β-lap were similar to those in the cell treated with β-lap alone. We previously reported that an increase in the G2 cell population after irradiation increased the cyclin B1-Cdc2 kinase activity, which in turn, accelerated the exit of cells from the G2 phase to mitosis (21). It is tempting to conclude that the progressive decline in the G2 cell population after β-lap treatment removed the necessity for an increase in the cyclin B1-Cdc2 kinase activity in both non-irradiated and irradiated cells.…”

Section: Discussionmentioning

confidence: 91%

“…The supernatant was mixed with isopropanol (1：1) and stored overnight at -20 o C. After centrifugation at 12,000×g for 20 min, the pellet was resuspended in TE buffer (10 mM Tris-HCl pH 7.4, 1 mM EDTA) and the RNA digested by the addition of 0.2 mg/ml DNase-free RNase. A15～20μg aliquot of DNA from each sample, as well as the DNA molecular weight marker, were subjected to electrophoresis on 1.5% agarose gel in TBE (89 mM Tris base, 89 mM boric acid, 2 mM EDTA) and the DNA stained with ethidium bromide (21).…”

Section: Methodsmentioning

confidence: 99%

Synergistic Effect of Ionizing Radiation and β-lapachone against RKO Human Colon Adenocarcinoma Cells

Kim

Ahn

et al. 2005

Cancer Res Treat

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Purpose: To reveal the interaction between β-Lapachone (β-lap) and ionizing radiation in causing cell death in RKO human colon adenocarcinoma cells, and to elucidate the potential usefulness of combined β-lap treatment and radiotherapy for cancer treatment. Materials and Methods:The cytotoxicities of various treatments were determined in vitro using clonogenic and apoptotic cell death. The changes in cell cycle distribution were studied using flow cytometry and an in vitro kinase assay. The tumor growth was studied using RKO tumors grown s.c. in the hind leg BALB/c-nuslc nude mice.Results: β-lap caused clonogenic cell death and rapid apoptosis in RKO cells in vitro, in a dose dependent manner. The repair of sublethal radiation damage was almost completely inhibited when cells were maintained in β-lap during the interval between the two-dose irradiation. Flow cytometry study demonstrated that β-lap

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Cell cycle progression and apoptosis after irradiation in an acidic environment

Abstract: We investigated the effect of an acidic environment on the radiation-induced G2/M arrest and apoptosis using RKO×C human colorectal cancer cells expressing wild-type p53 and RC10×1 cells, a subline of RKO×C cells deficient in p53 as well as p53 +/+ MEFs and p53 7/7

Cited by 38 publications

References 20 publications

Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation

Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation

Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted

Synergistic Effect of Ionizing Radiation and β-lapachone against RKO Human Colon Adenocarcinoma Cells

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