title: Blocking NF-κB sensitizes non-small cell lung cancer cells to histone deacetylase inhibitor induced extrinsic apoptosis through generation of reactive oxygen species.
abstract: NF-κB signalling is one of the main cell survival pathways that attenuate the anticancer efficacy of therapeutic drugs. Previous studies demonstrated that the histone deacetylase (HDAC) inhibitor induces apoptosis in some malignancies through multiple mechanisms including up-regulation of death receptors, disruption of Hsp90 function and generation of reactive oxygen species (ROS). However, HDAC inhibitor also induces a cell survival signal through NF-κB activation. In this report, we found that romidepsin, a class I HDAC inhibitor, induces NF-κB activation in A549 non-small-cell lung cancer (NSCLC) cells. We also found that inhibition of A549 cells with bortezomib (proteasome inhibitor) has blocked IκB degradation that leads to the loss of NF-κB activation and translocation which enhanced the romidepsin induced mitochondrial injury and sensitizes NSCLC cells to apoptosis. Romidepsin significantly enhances NF-κB reporter gene transcription and these effects were inhibited by bortezomib as determined by reporter gene assay. Consistently, the combined exposure of romidepsin and bortezomib reversed the effects on IκB degradation as evident with IL-8, p50 and p65 (NF-κB) expression. Apoptosis was markedly sensitized with greater ROS generation and more cell death in A549 cell lines. These events are most closely related in that bortezomib prevents the romidepsin mediated RelA acetylation and NF-κB activation, resulting in caspase activation. A strategy of blocking NF-κB activation to enhance HDAC inhibitor activity warrants further attention in NSCLC cells.
authors: Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli-620 024, Tamil Nadu, India.
authors: Selvaraju
authors: S
authors: Karthik
authors: Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli-620 024, Tamil Nadu, India.
authors: Renu
authors: R
authors: Sankar
authors: Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli-620 024, Tamil Nadu, India.
authors: Krishnamoorthy
authors: K
authors: Varunkumar
authors: Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli-620 024, Tamil Nadu, India.
authors: Chidambaram
authors: C
authors: Anusha
authors: Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli-620 024, Tamil Nadu, India. Electronic address: ravikumarbdu@gmail.com.
authors: Vilwanathan
authors: V
authors: Ravikumar
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001897:Boronic Acids; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D011719:Pyrazines; D017382:Reactive Oxygen Species; D000069286:Bortezomib; C087123:romidepsin; D020169:Caspases
keywords: A549; Bortezomib; NF-κB; NSCLC; Reactive oxygen species; Romidepsin