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Differential transactivation of human metallothionein-IIa in cisplatin-resistant and -sensitive cells

Academic Article
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Overview

authors

  • Yang, Y. Y.
  • Robbins, Paul D.
  • Lazo, J. S.

publication date

  • 1998

journal

  • Oncology Research  Journal

abstract

  • Cells with acquired anticancer drug resistance frequently exhibited broad cross-resistance to other anticancer agents. Increased human metallothionein (hMT) IIa transcription has been found in some cells with acquired resistance to cisplatin (CP). A panel of 5'hMT-IIa promoter deletions linked to the chloramphenicol acetyl transferase ((5'-hMT-IIaCAT) were used to demonstrate that certain cis-elements are important for the increased hMT-IIa transcription in CP-resistant cells (SCC25/CP) compared to CP-sensitive cells (SCC25). We further identified trans-acting factor differences between SCC25 and SCC25/CP cells using gel mobility shift assays. Significant increases in binding of specific factors to the -286 to -160 and -96 to -51 region were seen in CP-resistant SCC25/CP cells compared to sensitive SCC25 cells. Using cross-competition and super gel shift analyses, we identified enhanced Spl and AP-2 binding activity in SCC25/CP cells. By Western blot analysis and immunoprecipitation, we demonstrated that the level of Spl was unchanged between the two cells types whereas AP-2 was elevated twofold in SCC25/CP cells. Our results indicated that the selection of CP-resistant phenotype in SCC25/CP was accompanied by increased Spl and AP-2 DNA binding activities, which are likely not only to enhance hMT-IIa transcription but could also alter expression of other genes responsible for a broader anticancer drug cross-resistance. Thus, altered trans-acting factors could account for the complex cross-resistant phenotype found in some anticancer drug-resistant cells.

subject areas

  • Antineoplastic Agents
  • Carcinoma, Squamous Cell
  • Cell Nucleus
  • Chloramphenicol O-Acetyltransferase
  • Cisplatin
  • Drug Resistance, Neoplasm
  • Electrophoresis, Agar Gel
  • Genes, Reporter
  • Genetic Vectors
  • Head and Neck Neoplasms
  • Humans
  • Metallothionein
  • Neoplasm Proteins
  • Promoter Regions, Genetic
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
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Research

keywords

  • acquired resistance
  • cisplatin
  • cross-resistance
  • metallothionein IIa
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Identity

International Standard Serial Number (ISSN)

  • 0965-0407

PubMed ID

  • 9666516
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Additional Document Info

start page

  • 85

end page

  • 98

volume

  • 10

issue

  • 2

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