Unknown,Transcriptomics,Genomics,Proteomics

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Iron Chelators Treatment on DMS-53 Human Lung Cancer Cell

ABSTRACT: The molecular role of iron in gene expression remains poorly characterized. Moreover, the alterations in global gene expression after iron chelation remains unclear and are important to assess for understanding the molecular pathology of iron-depletion and the biological effects of iron chelators. We assessed the effect on whole genome gene expression of two iron chelators (desferrioxamine and Dp44mT). These studies are important for understanding the molecular and cellular effects of iron-depletion. The DMS-53 cells were incubated with either control medium or this medium containing DFO (250 µM) or Dp44mT (25 µM) for 24 h at 37oC. These concentrations were used since our previous studies demonstrated that under these conditions these chelators lead to up-regulation of iron-responsive genes such as the TfR1 after this incubation time. Moreover, the higher concentration of DFO was implemented due to its limited ability to permeate cell membranes. Total RNA was isolated from cells in 1 mL of TRIzol® reagent (Invitrogen). Samples were then prepared and hybridized to the Human Genome U133 Plus 2.0 430 2.0. The human GeneChip® U133 Plus 2.0 consists of greater than 47,000 transcripts and variants from over 38,500 well characterized human genes. On completion of hybridization and washing, microarray chips were scanned with the Affymetrix GeneChip® Scanner 3000 (Affymetrix).

ORGANISM(S): Homo sapiens

SUBMITTER: Yu Yu

PROVIDER: E-GEOD-26920 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Iron is required as a cofactor for many critical cellular enzymes involved in energy metabolism and cell proliferation and is thus essential for all living cells. To facilitate the rapid replication, the neoplastic cells have significantly higher levels of ribonucleotide reductase and the transferrin receptor 1 (TfR1) and many in vitro and in vivo studies have demonstrated that, compared to normal cells, cancer cells are more sensitive to iron (Fe) deprivation because of their marked Fe requirements. The higher Fe utilization by cancer cells provides a rationale for the selective antitumor activity of chelators. To date, Deferoxamine (DFO) is one of the most widely used iron chelator. In addition, DFO also has some antitumor activity. Moreover, novel chelators based on the di-2-pyridylketone thiosemicarbazone (DpT) scaffold, such as di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), induce iron sequestration and also form redox-active metal complexes that demonstrate potent and selective anti-tumor activity. Notably, Dp44mT and its analogs possess broad anti-cancer and anti-metastatic activity in vitro and in vivo against a variety of aggressive solid tumors. Understanding the mechanism of action of these ligands and their effect on the ER stress pathway will yield better clinical outcomes. It has been reported that iron depletion induced by Dp44mT and its metal complexes causes apoptosis by generating cytotoxic ROS and by inducing DNA strand breaks. The redox active complexes formed in lysosomes induce damages generating tumor cell cytotoxicity. The alterations in gene expression after iron depletion are complex. Moreover, in cultured cells Dp44mT resulted in marked up-regulation of the Fe-responsive tumor growth and metastasis suppressor Ndrg1 (N-myc downstream regulated gene-1). Therefore, Up-regulation of Ndrg1 may be another mechanism by which chelators inhibit cancer cell proliferation. Here we combine biochemistry, microscopy, flow cytometry and LC/MS-MS analyses to investigate cellular events induced by DFO and Dp44mT iron chelators on two human breast cancer cell lines, MDA-MB-231 and MDA-MB-157, in terms of proliferation, cell cycle, cytotoxicity and death. These experiments could potentially provide additional information in terms of the mechanism(s) of action of iron chelators in breast cancer cells.

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Iron Chelators Treatment on DMS-53 Human Lung Cancer Cell

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