RT Journal Article
SR Electronic
T1 Pharmacogenomic Approach Reveals a Role for the x<sub>c</sub><sup>-</sup> Cystine/Glutamate Antiporter in Growth and Celastrol Resistance of Glioma Cell Lines
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.109.162248
DO 10.1124/jpet.109.162248
A1 Anh-Nhan Pham
A1 Paul E Blower
A1 Omar Alvarado
A1 Ranadheer Ravula
A1 Peter Gout
A1 Ying Huang
YR 2009
UL http://jpet.aspetjournals.org/content/early/2009/12/09/jpet.109.162248.abstract
AB The xc- cystine/glutamate antiporter has been implicated in glutathione (GSH)-based chemoresistance as it mediates cellular uptake of cystine/cysteine for sustenance of intracellular GSH levels. Celastrol, isolated from a Chinese medicinal herb, is a novel heat shock protein 90 (Hsp90) inhibitor with potent anticancer activity against glioma in vitro and in vivo. In looking for correlations between growth-inhibitory potency of celastrol in NCI-60 cell lines and microarray expression profiles of most known transporters, we found that expression of SLC7A11, the gene encoding the light chain subunit of xc-, showed a strong negative correlation with celastrol activity. This novel gene-drug correlation was validated. In celastrol-resistant glioma cells that highly expressed SLC7A11, sensitivity to celastrol was consistently increased via treatment with xc- inhibitors, including glutamate, (S)-4-carboxyphenylglycine, sulfasalazine and SLC7A11 siRNA. The GSH synthesis inhibitor, buthionine sulfoximine, also increased celastrol sensitivity, whereas the GSH booster, N-acetylcysteine, suppressed its cytotoxicity. Furthermore, the glioma cell lines were dependent on xc--mediated cystine uptake for viability, since cystine omission from the culture medium resulted in cell death and treatment with sulfasalazine depleted GSH levels and inhibited their growth. Combined treatment of glioma cells with sulfasalazine and celastrol led to chemosensitization, as suggested by increased celastrol-induced cell cycle arrest, apoptosis and down-regulation of the Hsp90 client protein, EGFR. These results indicate that the xc- transporter provides a useful target for glioma therapy. xc- inhibitors such as sulfasalazine, an FDA-approved drug, may be effective both as an anticancer drug and as an agent for sensitizing gliomas to celastrol.The American Society for Pharmacology and Experimental Therapeutics