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, Steven Grant

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

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 μM SAHA for 24-48 hr resulted in a marked induction of mitchondrial damage (e.g., cytochrome c release) and apoptosis, events associated with downregulation 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 as well as by the JNK activator anisomycin. Interestingly, HDI-induced JNK activation was potentiated by pharmacologic MEK inhibition. Furthermore, HDI lethality was significantly diminished in cells ectopically expressing constitutively active MEK1, 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.

Original languageBritish English
Pages (from-to)544-551
Number of pages8
JournalCancer Biology and Therapy
Volume2
Issue number5
DOIs
StatePublished - Sep 2003

Keywords

  • Apoptosis
  • Bcr/Abl
  • Histone deacetylase
  • Inhibitors
  • JNK
  • Leukemia

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