Received for publication July 9, 2007.
Revised September 15, 2007.
Accepted for publication September 17, 2007.

Cystine-glutamate transporter SLC7A11 mediates resistance to geldanamycin but not to 17-AAG

Abstract

The cystine-glutamate transporter SLC7A11 has been implicated in chemoresistance, by supplying cystine to the cell for glutathione maintenance. In the NCI-60 cell panel, SLC7A11 expression shows negative correlation with growth inhibitory potency of geldanamycin, but not with its analogue 17-AAG, which differs in the C-17 substituent by replacing the methoxy moiety of geldanamycin with an amino group. Structure and potency analysis classified 18 geldanamycin analogues into two subgroups, "7-O/H"(C-17 methoxy or unsubstituted) and "7-N"(C-17 amino), showing distinct SLC7A11-correlation. We used three 17-O/H analogues and four 17-N analogues to test the role of the 17-substituents in susceptibility to SLC7A11-mediated resistance. In A549 cells, which are resistant to geldanamycin and strongly express SLC7A11, inhibition of SLC7A11 by (S)-4-carboxyphenylglycine or siRNA increased sensitivity to 17-O/H, but had no effect on 17-N analogues. Ectopic expression of SLC7A11 in HepG2 cells, which are sensitive to geldanamycin and express low SLC7A11, confers resistance to geldanamycin, but not to 17-AAG. Antioxidant N-acetylcysteine, a precursor for glutathione synthesis, completely suppressed cytotoxic effects of 17-O/H, but had no effect on 17-N analogues, while the prooxidant ascorbic acid had opposite effects. Compared to 17-AAG, geldanamycin led to significantly more intracellular reactive oxygen species (ROS) production, which was quenched by addition of N-acetylcysteine. We conclude that SLC7A11 confers resistance selectively to 17-O/H (e.g., geldanamycin) but not to 17-N (e.g., 17-AAG) analogues partly due to differential dependence on ROS for cytotoxicity. Distinct mechanisms could significantly affect antitumor response and organ toxicity of these compounds in vivo.

Key words: Amino Acid, Genetics, Glutathione, Oxidative stress/antioxidants, Resistance

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