Modulation of multidrug resistance in cancer cells by the E3 ubiquitin ligase seven-in-absentia homologue 1

J Pathol. 2008 Mar;214(4):508-14. doi: 10.1002/path.2312.

Abstract

Seven-in-absentia homologue 1 (Siah1) is an E3 ubiquitin ligase that regulates the ubiquitination and proteasome-dependent degradation of a number of proteins. Here we report that Siah1 modulates multidrug resistance 1 (MDR1)/P-glycoprotein-mediated drug resistance in the cancer cell lines examined. Siah1, but not its ligase-dead mutant, down-regulates MDR1/P-glycoprotein and sensitizes the multidrug-resistant cells to chemotherapeutic agents. Mechanistically, Siah1 does not promote P-glycoprotein degradation but decreases its expression transcriptionally by promoting c-Jun transcription factor binding to the activator protein 1 (AP1) site in the MDR1 promoter. Moreover, Siah1 triggers c-Jun NH2-terminal kinase (JNK) activation, leading to enhanced phosphorylation of c-Jun, and the JNK/c-Jun signalling axis is critical for Siah1 to down-regulate MDR1/P-glycoprotein expression. These findings demonstrate a previously unidentified role for Siah1 in regulating MDR1/P-glycoprotein expression through the JNK/c-Jun pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
  • Down-Regulation
  • Drug Resistance, Multiple* / genetics
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasm Proteins / physiology
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nuclear Proteins / physiology*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-jun / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Signal Transduction
  • Transcription Factor AP-1 / metabolism
  • Tumor Cells, Cultured
  • Ubiquitin-Protein Ligases / physiology*

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor AP-1
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins