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Increased expression of cdc2 inhibits transport function of RLIP76 and promotes apoptosis

Sharad S Singhal1, Sushma Yadav, Rit Vatsyayan

  • 1Department of Molecular Biology and Immunology, 3500 Camp Bowie Blvd., University of North Texas Health Science Center, Fort Worth, TX 76107-2699, United States. ssinghal@hsc.unt.edu

Cancer Letters
|April 21, 2009
PubMed

Insights

The study shows that Cdc2 kinase inhibits the RLIP76 transporter, which is overexpressed in cancers. This inhibition increases doxorubicin accumulation in cancer cells, offering a potential strategy to overcome drug resistance.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • RLIP76 is a transporter for glutathione-electrophile-conjugates (GS-E) and drugs, overexpressed in various cancers.
  • Cdc2 kinase interacts with RLIP76 during mitosis, inhibiting endocytosis.

Purpose of the Study:

  • To investigate the effect of purified Cdc2 on RLIP76 transport activity.
  • To explore the potential of modulating RLIP76-mediated drug resistance using Cdc2.

Main Methods:

  • Purification of Cdc2 kinase.
  • Reconstitution of RLIP76 into artificial liposomes.
  • Assay of doxorubicin (DOX) and dinitro-phenyl S-glutathione (DNP-SG) transport.
  • Liposomal delivery of Cdc2 to H358 cells.

Main Results:

  • Cdc2 inhibited both DOX and DNP-SG transport by RLIP76 in a concentration-dependent manner.
  • Liposomal Cdc2 induced apoptosis in H358 cells.
  • Cdc2 treatment increased intracellular doxorubicin accumulation and decreased its efflux.

Conclusions:

  • Cdc2 can inhibit the transport activity of RLIP76.
  • Inhibition of RLIP76 by Cdc2 may represent a novel strategy to overcome accumulation-deficient drug resistance in cancer.

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