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PI3-kinase and mTOR inhibitors differently modulate the function of the ABCG2 multidrug transporter

Csilla Hegedüs1, Krisztina Truta-Feles, Géza Antalffy

  • 1Membrane Research Group of the Hungarian Academy of Sciences, Department of Biophysics, Semmelweis University and National Blood Center, Budapest, Hungary.

Biochemical and Biophysical Research Communications
|March 28, 2012
PubMed

Insights

The PI3-kinase/Akt pathway regulates the ABCG2 transporter. However, PI3-kinase inhibitors LY294002 and rapamycin directly inhibit ABCG2 function, not just their target kinases.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • ATP-binding cassette (ABC) transporter ABCG2 is crucial for tissue detoxification and multidrug resistance in cancer.
  • Identifying regulators of ABCG2 is vital for understanding and overcoming drug resistance.
  • The PI3-kinase/Akt signaling pathway influences ABCG2 expression and localization.

Purpose of the Study:

  • To investigate the direct effects of PI3-kinase/Akt pathway inhibitors on ABCG2 transporter function.
  • To determine if pharmacological inhibitors of this pathway interact directly with ABCG2.

Main Methods:

  • Utilized pharmacological inhibitors: LY294002 (PI3-kinase inhibitor), rapamycin (mTOR inhibitor), and wortmannin (PI3-kinase inhibitor).
  • Assessed the direct functional modulation of ABCG2 transporter activity by these agents.
  • Compared the effects of different PI3-kinase inhibitors on ABCG2.

Main Results:

  • LY294002 and rapamycin directly inhibit ABCG2 transporter function, beyond their kinase inhibitory activity.
  • Wortmannin, another PI3-kinase inhibitor, did not show direct interaction with ABCG2.
  • This suggests a direct functional cross-talk between these inhibitors and the ABCG2 transporter.

Conclusions:

  • Pharmacological inhibitors targeting the PI3-kinase/Akt/mTOR pathway can directly modulate ABCG2 transporter function.
  • Direct functional inhibition of ABCG2 by LY294002 and rapamycin must be considered.
  • Future studies dissecting PI3-kinase/Akt/mTOR signaling should account for potential direct ABCG2 modulation.

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