Glutathione S‐transferase M1 inhibits dexamethasone‐induced apoptosis in association with the suppression of Bim through dual mechanisms in a lymphoblastic leukemia cell line
(Cancer Sci 2010; 101: 767–773) Glutathione S‐transferase μ (GSTM1) is mainly known as a detoxification enzyme but it has also been shown to be a negative regulator of apoptosis‐related signaling cascades. Recently GSTM1 has been reported to be a significant risk factor for hematological relapse in...
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Veröffentlicht in: | Cancer science 2010-03, Vol.101 (3), p.767-773 |
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Zusammenfassung: | (Cancer Sci 2010; 101: 767–773)
Glutathione S‐transferase μ (GSTM1) is mainly known as a detoxification enzyme but it has also been shown to be a negative regulator of apoptosis‐related signaling cascades. Recently GSTM1 has been reported to be a significant risk factor for hematological relapse in childhood acute lymphoblastic leukemia, although the underlying mechanism remains largely unknown. Glucocorticoids play a crucial role in the treatment of childhood acute lymphoblastic leukemia, therefore we hypothesized that GSTM1 plays important roles in glucocorticoid‐induced apoptotic pathways. To clarify the relationship between GSTM1 and drug resistance, GSTM1 was transfected into a T‐acute lymphoblastic leukemia cell line, CCRF‐CEM (CEM), and we established the GSTM1‐expressing cell lines CEM/M1‐4 and CEM/M1‐9. Transduction of GSTM1 into CEM selectively decreased cellular sensitivity to dexamethasone in a manner that was independent of glutathione conjugation, but was due to apoptosis inhibition. Dexamethasone‐induced p38‐MAPK and Bim activation were concomitantly suppressed. Interestingly, nuclear factor kappa b (NF‐κB) p50 activity was upregulated in GSTM1‐expressing CEM. Inhibition of NF‐κB by the pharmacological agent BAY11‐7082 greatly enhanced the sensitivity of the GSTM1‐expressing CEM to dexamethasone and was accompanied by an increase in Bim expression. Thus, we propose that GSTM1, a novel regulator of dexamethasone‐induced apoptosis, causes dexamethasone resistance by suppression of Bim through dual mechanisms of both downregulation of p38‐MAPK and upregulation of NF‐κB p50. |
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ISSN: | 1347-9032 1349-7006 1349-7006 |
DOI: | 10.1111/j.1349-7006.2009.01432.x |