Low-dose anisomycin sensitizes glucocorticoid-resistant T-acute lymphoblastic leukemia CEM-C1 cells to dexamethasone-induced apoptosis through activation of glucocorticoid receptor and p38-MAPK/JNK

Abstract

Glucocorticoid (GC) resistance in children with acute lymphoblastic leukemia (ALL) usually resulted in the failure of treatment. Exploring new agents to overcome GC resistance is important. Here we reported for the first time that low-dose anisomycin has the potential to sensitize GC-resistant T-ALL CEM-C1 cells to dexamethasone (DEX). Compared with the use of DEX or low-dose anisomycin alone, co-treatment with them resulted in a significant increase of growth inhibition, apoptosis and cell cycle arrest in CEM-C1 cells through induction of activated caspase-3 and up-regulation of Bim, p21and p27, and down-regulation of Mcl-1, Bcl-2, c-myc, cyclin A and cyclin D1. Furthermore, co-treatment remarkably activated glucocorticoid receptor (GR), p38-MAPK and JNK, and all of them were canceled only by the GR inhibitor RU486, indicating GR might be an at the upstream of GR–p38-MAPK/JNK pathway. We conclude that low-dose anisomycin sensitizes GC-resistant CEM-C1 cells to DEX and this effect is mediated, at least in part, by activation of the GR–p38-MAPK/JNK signaling pathway.

Keywords::

• Anisomycin
• acute lymphoblastic leukemia (ALL)
• glucocorticoid resistance
• p38-MAPK
• JNK
• glucocorticoid receptor

Acknowledgements

This study was supported by grants from the Department of Science and Technology of Sichuan Province, China (No. 2008JY0029-1 and No. 07FG002-024), a grant from the Doctoral Project for Young Teachers of the Ministry of Education, China (No. 20120181120050) and research funds from the program for Chang Jiang Scholars and Innovative-Research Team in University (No. IRT0935). We thank Professor E. Brad Thompson (Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX) for his kind gifts of ALL-CEM-C1 and CEM-C7 cell lines.

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