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Research Paper
Induction of Apoptosis in BCR/ABL+ Cells By Histone Deacetylase Inhibitors Involves Reciprocal Effects on the RAF/MEK/ERK and JNK Pathways
Chunrong Yu, Mark Subler, Mohamed Rahmani, Erin Reese, Geoffrey Krystal, Daniel Conrad, Paul Dent and Steven Grant
volume 2 | issue 5
sept/oct 2003Pages: 544-551
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Signal transduction events regulating induction of apoptosis by the histone deacetylase inhibitors (HDIs) sodium butyrate (SB) and SAHA have been examined in Bcr/Abl+ human leukemia cells (K562, LAMA 84). Exposure of K562 cells to >= 3.0 mM SB or 3.0 mM SAHA for 24-48 hr resulted in a marked induction of mitchondrial damage (e.g., cytochrome c release) and apoptosis, events associated with down-regulation of Bcr/Abl and Raf-1, induction of p21CIP1, inactivation of MEK1/2, ERK1/2, and p70S6K, and a dramatic increase in JNK activation. HDI-mediated apoptosis was attenuated by pharmacologic JNK inhibitors and enhanced by the MEK1/2 inhibitor U0126, which increased JNK activation, as well as by the JNK activator anisomycin. Furthermore, HDI lethality was significantly diminished in cells ectopically expressing constitutively active MEK1/2, confirming a functional role for MEK/ERK inactivation in HDI-mediated apoptosis. Similar events were observed in Bcr/Abl+ LAMA 84 cells. Lastly, the free radical scavenger L-N-acetylcysteine (LNAC) attenuated HDI-mediated ROS generation, JNK activation, and apoptosis. Together, these findings support a model in which induction of apoptosis in Bcr/Abl+ cells by HDIs involves coordinate inactivation of the cytoprotective Raf/MEK/ERK pathway in conjunction with the ROS-dependent activation of JNK.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.