Unknown,Transcriptomics,Genomics,Proteomics

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Genome-wide analysis of the effects of the novel mithramycin analogue DIG-MSK on human A2780 ovarian carcinoma cells

ABSTRACT: The effects of demycarosyl-3D-M-NM-2-D-digitoxosyl-mithramycin SK (DIG-MSK; EC-8042), a novel analogue of the antitumor antibiotic mithramycin A, on gene transcription were examined in human A2780 ovarian carcinoma cells. DIG-MSK down-regulated a different set of genes depending on the drug concentration. Moreover, several genes were significantly up-regulated. These results are rationalized in terms of DIG-MSK competition with Sp1 transcription factor for binding to consensus C/G-rich tracts encompassed in gene promoters. Human A2780 ovarian carcinoma cells were treated with either 8 nM or 80 nM DIG-MSK for 24 h, and RNA was extracted from treated cells as well as from untreated (control) cells.

ORGANISM(S): Homo sapiens

SUBMITTER: JosM-CM-) Portugal

PROVIDER: E-GEOD-46926 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genome-wide modulation of gene transcription in ovarian carcinoma cells by a new mithramycin analogue.

Vizcaíno Carolina C Núñez Luz-Elena LE Morís Francisco F Portugal José J

PloS one 20140811 8

Ovarian cancer has a poor prognosis due to intrinsic or acquired resistance to some cytotoxic drugs, raising the interest in new DNA-binding agents such as mithramycin analogues as potential chemotherapeutic agents in gynecological cancer. Using a genome-wide approach, we have analyzed gene expression in A2780 human ovarian carcinoma cells treated with the novel mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK) that binds to C+G-rich DNA sequences. Nanomolar concentrat ...[more]

PMID: 25110883

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Project description:Drug resistance poses a major challenge to ovarian cancer treatment. Understanding mechanisms of drug resistance is important for finding new therapeutic targets. In the present work, a cisplatin-resistant ovarian cancer cell line A2780-DR was established with a resistance index of 6.64. The cellular accumulation of cisplatin was significantly reduced in A2780-DR cells as compared to A2780 cells consistent with the general character of drug resistance. Quantitative proteomic analysis identified 340 differentially expressed proteins between A2780 and A2780-DR cells, which involve in diverse cellular processes, including metabolic process, cellular component biogenesis, cellular processes and stress responses. Expression levels of Ras-related proteins Rab 5C and Rab 11B in A2780-DR cells were lower than those in A2780 cells as confirmed by real-time quantitative PCR and western blotting. The short hairpin (sh)RNA-mediated knockdown of Rab 5C in A2780 cells resulted in markedly increased resistance to cisplatin whereas overexpression of Rab 5C in A2780-DR cells increases sensitivity to cisplatin, demonstrating that Rab 5C-dependent endocytosis plays an important role in cisplatin resistance. Our results also showed that expressions of glycolytic enzymes PKM, GPI, Aldolase, LDH, and PGK were down-regulated in drug resistant cells, indicating drug resistance in ovarian cancer is directly associated with a decrease in glycolysis. Furthermore, it was found that glutathione reductase were up-regulated in A2780-DR, while vimentin, HSP90, and Annexin A1 and A2 were down-regulated. Taken together, our results suggest that drug resistance in ovarian cancer cell line A2780 is caused by multifactorial traits, including the down-regulation of Rab 5C-dependent endocytosis of cisplatin, glycolytic enzymes and vimentin, and up-regulation of antioxidant proteins, suggesting Rab 5C is a potential target for treatment of drug-resistant ovarian cancer. This constitutes a further step towards a comprehensive understanding of drug resistance in ovarian cancer.

Dataset Information

Genome-wide analysis of the effects of the novel mithramycin analogue DIG-MSK on human A2780 ovarian carcinoma cells

Publications

Genome-wide modulation of gene transcription in ovarian carcinoma cells by a new mithramycin analogue.

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