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Oligomerization domain of the multidrug resistance-associated transporter ABCG2 and its dominant inhibitory activity

Junkang Xu1, Hui Peng, Qun Chen

  • 1Department of Pharmacology and Toxicology, Indiana University Cancer Center, Walther Oncology Center/Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

Cancer Research
|May 8, 2007
PubMed

Insights

Overexpression of human ATP-binding cassette transporter ABCG2 causes cancer drug resistance. Researchers identified its oligomerization domain (TM5-loop-TM6) which may be a therapeutic target to overcome resistance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The human ATP-binding cassette transporter ABCG2 contributes to multidrug resistance in cancer by exporting anticancer drugs.
  • ABCG2 is typically considered a homodimer, but recent evidence suggests it may form higher-order oligomers.

Purpose of the Study:

  • To map the oligomerization domain of human ABCG2.
  • To investigate the role of this domain in ABCG2 function and oligomerization.
  • To explore therapeutic potential targeting ABCG2 oligomerization.

Main Methods:

  • Expression of ABCG2 oligomerization domain in HEK293 cells.
  • Analysis of oligomerization state using biochemical assays.
  • Assessment of drug efflux and resistance inhibition by the oligomerization domain.

Main Results:

  • The oligomerization domain of human ABCG2 was mapped to its transmembrane domain (TM5-loop-TM6).
  • This domain, when expressed alone, forms a homododecamer.
  • The isolated domain inhibits the drug efflux and resistance functions of full-length ABCG2, likely by disrupting oligomer formation.

Conclusions:

  • Human ABCG2 likely functions as a homo-oligomer through interactions within the TM5-loop-TM6 domain.
  • Targeting ABCG2 oligomerization presents a potential therapeutic strategy to overcome drug resistance in cancer treatment.

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