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

Ya Yun Yang, Paul D. Robbins, John S. Lazo

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 gene ((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 Sp1 and AP-2 binding activity in SCC25/CP cells. By Western blot analysis and immunoprecipitation, we demonstrated that the level of Sp1 was unchanged between the two cell 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 Sp1 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.

Original languageEnglish (US)
Pages (from-to)85-98
Number of pages14
JournalOncology Research
Volume10
Issue number2
StatePublished - 1998
Externally publishedYes

Keywords

  • Acquired resistance
  • Cisplatin
  • Cross-resistance
  • Metallothionein IIa

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