Involvement of HDAC1 and the PI3K/PKC signaling pathways in NF-kappaB activation by the HDAC inhibitor apicidin.
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-kappaB 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-kappaB activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-kappaB 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-kappaB activation or IL-8 expression. In addition, our data show that the early expression of TNF-alpha does not lead to activation of NF-kappaB, because disruption of TNF-alpha activity by a neutralizing antibody does not affect nuclear translocation of NF-kappaB, IkappaBalpha degradation or reporter gene activation by apicidin. However, this activation of NF-kappaB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-kappaB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-kappaB reporter gene activity. Collectively, our results suggest that activation of NF-kappaB 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.
Kim
Yong Kee
YK
Department of Pharmacology, Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea. yksnbk@kwandong.ac.kr
Seo
Dong-Wan
DW
Kang
Dong-Won
DW
Lee
Hoi Young
HY
Han
Jeung-Whan
JW
Kim
Su-Nam
SN
D000730:Androstadienes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006367:HeLa Cells; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D012097:Repressor Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000077191:Wortmannin; D000099186:Histone Deacetylase 3
D000730:Androstadienes; D002070:Butadienes; D002867:Chromones; D005419:Flavonoids; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D016209:Interleukin-8; D009025:Morpholines; D016328:NF-kappa B; D009570:Nitriles; D010456:Peptides, Cyclic; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; D000099186:Histone Deacetylase 3; C113580:U 0126; C102351:apicidin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C110550:HDAC1 protein, human; C400300:HDAC4 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one