A microarray-based, integrated approach to identify novel regulators of cancer drug response and apoptosis

Brachat, Arndt; Pierrat, Benoı̂t; Xynos, Alexandros; Brecht, Karin; Simonen, Mika; Brüngger, Adrian; Heim, Jutta

doi:10.1038/sj.onc.1206016

Cited by 29 publications

(24 citation statements)

References 30 publications

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“…In contrast, we have shown that death receptor signaling by CHX/TNF-α, the broad-spectrum protein kinase inhibitor STS, camptothecin, a topoisomerase inhibitor inducing DNA strand breaks, or paclitaxel, a drug stabilizing microtubules, did not induce alpha globin expression. 17 While NIH3T3 cells showed similar alpha globin expression profiles after cisplatin and STS treatment as FL5.12 cells, HeLa cells displayed an exactly opposite regulation. This suggests that upregulation of alpha globin is not an unspecific signal for stress but specific for certain apoptotic pathways, and depends on the cell type.…”

Section: Discussionmentioning

confidence: 95%

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Upregulation of alpha globin promotes apoptotic cell death in the hematopoietic cell line FL5.12

2005

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The function of alpha globin in the context of oxygen transport in erythroid cells is well described. Recently the expression of alpha globin was shown to be upregulated upon specific apoptotic stimuli like cytokine deprivation or cisplatin treatment in the hematopoietic pro-B cell line, FL5.12. In contrast to alpha globin, beta globin or globin-like genes were expressed at a very low level or were not expressed at all. Further, we found that alpha globin was not associated with heme. Apoptotic cells neither produced hemoglobin nor displayed a phenotype of cells differentiating down the erythroid lineage. Also other cell lines of variable differentiation status (NIH3T3, HeLa, K562) upregulated alpha globin during treatment with apoptosis-inducing agents. Under IL-3-deprived conditions GFP-alpha globin accelerated the progression of apoptosis comparable to GFP-Bax. GFP-alpha globin was expressed at a low level and enrichment of FL5.12 cells expressing GFP-alpha globin was difficult even in the presence of IL-3. Caspase-8, -9 and -3 as well as the proapoptotic factor Bax and cytochrome c were activated. Antisense alpha globin downregulated the expression of endogenous alpha globin und reduced caspase activity. Taken together these data indicate that alpha globin is a new and crucial factor in apoptosis especially supporting the mitochondrial pathway.

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Section: Discussionmentioning

confidence: 95%

“…16 FL5.12 cells ectopically expressing alpha globin displayed accelerated apoptosis progression and increased caspase activity. 17 The primary objective of the present study was to analyze more closely the function of alpha globin in PCD. We compared wildtype FL5.12 cells with cells expressing GFP-alpha globin or antisense alpha globin.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of alpha globin promotes apoptotic cell death in the hematopoietic cell line FL5.12

2005

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“…It is important to note that microarray analyses in mammals include tissue taken directly from laboratory animals (Huang et al 2004;Ganter et al 2005), tissue biopsies (Takata et al 2005), or cell lines (Brachat et al 2002). Unfortunately these studies are limited due to the inevitable sacrifice of large numbers of mammalian subjects or by the availability of tissues and impractability of many experimental manipulations.…”

Section: Mtx-induced Developmental Effectsmentioning

confidence: 99%

A role for Drosophila in understanding drug-induced cytotoxicity and teratogenesis

Affleck

Walker

2008

Cytotechnology

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Drosophila research has been and continues to be an essential tool for many aspects of biological scientific research and has provided insight into numerous genetic, biochemical, and behavioral processes. As well, due to the remarkable conservation of gene function between Drosophila and humans, and the easy ability to manipulate these genes in a whole organism, Drosophila research has proven critical for studying human disease and the physiological response to chemical reagents. Methotrexate, a widely prescribed pharmaceutical which inhibits dihydrofolate reductase and therefore folate metabolism, is known to cause teratogenic effects in human fetuses. Recently, there has been resurgence in the use of methotrexate for inflammatory diseases and ectopic or unwanted pregnancies thus, increasing the need to fully understand the cytotoxicity of this pharmaceutical. Concerns have been raised over the ethics of studying teratogenic drugs like methotrexate in mammalian systems and thus, we have proposed a Drosophila model. We have shown that exposure of female Drosophila to methotrexate results in progeny with developmental abnormalities. We have also shown that methotrexate exposure changes the abundance of many fundamental cellular transcripts.Expression of a dihydrofolate reductase with a reduced affinity for methotrexate can not only prevent much of the abnormal transcript profile but the teratogenesis seen after drug treatment. In the future, such studies may generate useful tools for mammalian antifolate ''rescue'' therapies.

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“…The gene encoding TP53INP1 is ubiquitously expressed, with higher expression levels in the thymus and other lymphoid organs (7). In vitro, TP53INP1 expression is up-regulated in different cell types upon treatment with agents inducing cell proliferation arrest and/or apoptosis, including oxidative stress agents (3,25,35,39,55,60,64,70). TP53INP1 expression is induced by p53, which exerts its function mainly by inducing transcription of target genes involved in cell cycle arrest and apoptosis, as part of the cell response to genotoxic stress (39,59).…”

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confidence: 99%

Colitis and Colitis-Associated Cancer Are Exacerbated in Mice Deficient for Tumor Protein 53-Induced Nuclear Protein 1

Gommeaux

Cano

García

et al. 2007

Molecular and Cellular Biology

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Tumor protein 53-induced nuclear protein 1 (TP53INP1) is an antiproliferative and proapoptotic protein involved in cell stress response. To address its physiological roles in colorectal cancer and colitis, we generated and tested the susceptibility of Trp53inp1-deficient mice to the development of colorectal tumors induced by injection of the carcinogen azoxymethane followed by dextran sulfate sodium (DSS)-induced chronic colitis. Trp53inp1-deficient mice showed an increased incidence and multiplicity of tumors compared to those of wild-type (WT) mice. Furthermore, acute colitis induced by DSS treatment was more severe in Trp53inp1-deficient mice than in WT mice. Treatment with the antioxidant N-acetylcysteine prevented colitis and colitisassociated tumorigenesis more efficiently in WT mice than in Trp53inp1-deficient mice, suggesting a higher oxidative load in the latter. Consistently, we demonstrated by electron spin resonance and spin trapping that colons derived from deficient mice produced more free radicals than those of the WT during colitis and that the basal blood level of the antioxidant ascorbate was decreased in Trp53inp1-deficient mice. Collectively, these results indicate that the oxidative load is higher in Trp53inp1-deficient mice than in WT mice, generating a more-severe DSS-induced colitis, which favors development of colorectal tumors in Trp53inp1-deficient mice.

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A microarray-based, integrated approach to identify novel regulators of cancer drug response and apoptosis

Cited by 29 publications

References 30 publications

Upregulation of alpha globin promotes apoptotic cell death in the hematopoietic cell line FL5.12

Upregulation of alpha globin promotes apoptotic cell death in the hematopoietic cell line FL5.12

A role for Drosophila in understanding drug-induced cytotoxicity and teratogenesis

Colitis and Colitis-Associated Cancer Are Exacerbated in Mice Deficient for Tumor Protein 53-Induced Nuclear Protein 1

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