Contribution of disruption of the nuclear factor-kappaB pathway to induction of apoptosis in human leukemia cells by histone deacetylase inhibitors and flavopiridol.
نویسندگان
چکیده
Interactions between the cyclin-dependent kinase inhibitor flavopiridol and the histone deacetylase inhibitors (HDACIs) sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) have been examined in human leukemia cells in relation to effects on nuclear factor kappaB (NF-kappaB) activation. Exposure (24 h) of U937 human leukemia cells to NaB (1 mM) or SAHA (1.5 microM) resulted in a marked increase in NF-kappaB DNA binding, effects that were essentially abrogated by coadministration of flavopiridol (100 nM). These events were accompanied by a marked increase in mitochondrial injury, caspase activation, and apoptosis. Mutant cells expressing an IkappaBalpha super-repressor exhibited impairment of NF-kappaB DNA binding in response to HDACIs and a significant although modest increase in apoptosis. However, disruption of the NF-kappaB pathway also increased mitochondrial injury and caspase activation in response to flavopiridol and to an even greater extent to the combination of flavopiridol and HDACIs. Coadministration of flavopiridol with HDACIs down-regulated the X-linked inhibitor of apoptosis (XIAP), Mcl-1, and p21CIP1/WAF1 and activated c-Jun NH2-terminal kinase; moreover, these effects were considerably more pronounced in IkappaBalpha mutants. Similar responses were observed in U937 mutant cells stably expressing RelA/p65 small interfering RNA. In all cases, flavopiridol was significantly more potent than genetic interruption of the NF-kappaB cascade in promoting HDACI-mediated lethality. Together, these findings are consistent with the notion that although inhibition of NF-kappaB activation by flavopiridol contributes to antileukemic interactions with HDACIs, other NF-kappaB-independent flavopiridol actions (e.g., down-regulation of Mcl-1, XIAP, and p21CIP1/WAF1) play particularly critical roles in this phenomenon.
منابع مشابه
Contribution of Disruption of the Nf-κb Pathway to Induction of Apoptosis in Human Leukemia Cells by Histone Deacetylase Inhibitors and Flavopiridol
متن کامل
Effect of trichostatin A on histone deacetylase 1 (HDAC 1) and CIP/KIP (p21CIP1/WAF1, p27KIP1, and p57KIP2) gene expression, cell growth inhibition and apoptosis induction in lung cancer COR-L105 cell line. Abstract
Effect of trichostatin A on histone deacetylase 1 (HDAC 1) and CIP/KIP (p21CIP1/WAF1, p27KIP1, and p57KIP2) gene expression, cell growth inhibition and apoptosis induction in lung cancer COR-L105 cell line. Abstract Background: Lung cancer is one the leading cause of cancer-related death worldwide, with more than 1.2 million deaths each year. In addition to genetic mutations, epigenetic modif...
متن کاملEffect of valproic acid on JAK/STAT pathway, SOCS1, SOCS3, Bcl-xL, c-Myc, and Mcl-1 gene expression, cell growth inhibition and apoptosis induction in human colon cancer HT29 cell line.
Background and aim: Cytokines are a large family of protein messengers. These proteins induce various cellular responses. Janus kinases (JAKs) are mediators of cytokine, activated JAKs phosphorylate signal transducers, and activators of transcription (STAT) proteins that regulate cell differentiation, proliferation, and apoptosis. Aberrant JAK/STAT signaling is involved in the oncogenesis of se...
متن کاملEffects of Trichostatin A on the Histone Deacetylases (HDACs), Intrinsic Apoptotic Pathway, p21/Waf1/Cip1, and p53 in Human Neuroblastoma, Glioblastoma, Hepatocellular Carcinoma, and Colon Cancer Cell Lines
Background: The aberrant and altered patterns of gene expression play an important role in the biology of cancer and tumorigenesis. DNA methylation and histone deacetylation are the most studied epigenetic mechanisms. Histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA) and trichostatin A (TSA) are a group of anticancer compounds for the treatment of solid and hematological canc...
متن کاملHDAC Inhibitors and Heat Shock Proteins (Hsps)
Epigenetic alterations, including DNA acetylation, hypermethylation and hypomethylation, and the associated transcriptional changes of the affected genes are central to the evolution and progression of various human cancers, including pancreatic cancer. Cancer-associated epigenetic alterations are attractive therapeutic targets because such epigenetic alterations, unlike genetic changes, are po...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Molecular pharmacology
دوره 66 4 شماره
صفحات -
تاریخ انتشار 2004