Involvement of HDAC1 and the PI3K/PKC signaling pathways in NF-{kappa}B activation by the HDAC inhibitor apicidin
- Department of Pharmacology, Kwandong University College of Medicine, Gangneung 210-701 (Korea, Republic of)
- Department of Molecular Bioscience, Kangwon National University, Chuncheon 200-701 (Korea, Republic of)
- College of Medicine, Konyang University, Daejeon 302-718 (Korea, Republic of)
- College of Pharmacy, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of)
- KIST Gangneung Institute, Gangneung 210-340 (Korea, Republic of)
Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-{kappa}B as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-{kappa}B activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-{kappa}B and the expression of its target genes, IL-8 and TNF-{alpha}. TNF-{alpha} expression by apicidin is induced at earlier time points than NF-{kappa}B activation or IL-8 expression. In addition, our data show that the early expression of TNF-{alpha} does not lead to activation of NF-{kappa}B, because disruption of TNF-{alpha} activity by a neutralizing antibody does not affect nuclear translocation of NF-{kappa}B, I{kappa}B{alpha} degradation or reporter gene activation by apicidin. However, this activation of NF-{kappa}B requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-{kappa}B seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-{kappa}B reporter gene activity. Collectively, our results suggest that activation of NF-{kappa}B signaling by apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of apicidin.
- OSTI ID:
- 20854451
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 347, Issue 4; Other Information: DOI: 10.1016/j.bbrc.2006.06.196; PII: S0006-291X(06)01550-6; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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