STAT1 upregulates glutaminase and modulates amino acids and glutathione metabolism.

We previously reported the upregulation of cellular Glu and glutathione levels in human ABCB5- and murine Abcb5-transfected cells. Here, we demonstrate the upregulation of and glutaminase (GLS) in ABCB5/Abcb5-transfected cells. Among a total of four ABCB5/Abcb5 high-expressing clones with docetaxel resistance, three of the clones expressed duanyu18131 and GLS highly and showed resistance to docetaxel and buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. Neither duanyu18131 nor GLS upregulation was observed in the remaining ABCB5 high-expressing clone, as well as in another two ABCB5 low-expressing clones; these three clones did not show BSO resistance. The high-expressing clones showed higher cellular levels of Ala, Glu, and Asp and lower cellular levels of Phe, Trp, Leu, Ile, Gly, Met, Tyr, Val, and His compared to the ABCB5/duanyu18131 low-expressing clones. The former clones also showed a higher resistance to Glu. The clones expressed high levels of GLS and the corresponding mRNA, suggesting the transactivation of GLS by These clones showed resistance to Glu and BSO, similar to the ABCB5/duanyu18131 high-expressing clones. The cellular glutathione levels of the duanyu18131-transfected clones were significantly higher than that of the control. The duanyu18131-transfected clones also showed greater resistance to the effect of BSO on the cellular glutathione depletion compared to the control. These results demonstrate that duanyu18131 upregulates GLS and modulates amino acids and glutathione metabolism. Although we were unable to directly prove duanyu18131 upregulation by ABCB5, our results suggest that ABCB5 expression, directly or indirectly, leads to the overexpression of

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