title: Inhibition of nuclear factor-kappaB augments antitumor activity of adenovirus-mediated melanoma differentiation-associated gene-7 against lung cancer cells via mitogen-activated protein kinase kinase kinase 1 activation.
abstract: Nuclear factor-kappaB (NF-kappaB) activation promotes cell survival and growth. Reports show that chemotherapeutic agents and cytokines that are used for cancer therapy activate NF-kappaB expression in tumor cells and its suppression enhanced the antitumor activity. We hypothesized that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda7/IL-24) induces NF-kappaB expression and that inhibition of this expression results in enhanced tumor cell killing. Treatment of human lung tumor (H1299 and A549) cells with Ad-mda7 resulted in NF-kappaB activation in a dose- and time-dependent manner before activation of cell death pathways. To establish that inhibition of Ad-mda7-mediated NF-kappaB activation results in enhanced tumor cell killing, H1299 cells that overexpress the dominant-negative I kappa B alpha (dnI kappa B alpha) were treated with Ad-mda7 in vitro. An enhanced growth arrest and apoptosis was observed in Ad-mda7-treated H1299-dnI kappa B alpha compared with H1299-Neo cells. This Ad-mda7-mediated enhanced killing of H1299-dnI kappa B alpha cells involved cleavage of mitogen-activated protein kinase kinase kinase 1 (MEKK1) and caspase-3 in a feedback loop mechanism. The inhibition of MEKK1 or caspase-3 cleavage in H1299-dnI kappa B alpha cells resulted in reduced Ad-mda7-mediated cell killing. In vivo, the treatment of H1299-dnI kappa B alpha s.c. tumors with Ad-mda7 resulted in increased drug sensitivity and delayed the tumor growth rate compared with Ad-mda7-treated H1299-Neo tumors. Molecular analysis of Ad-mda7-treated H1299-dnI kappa B alpha tumors showed increased MEKK1 cleavage and activation of caspase-3 compared with Ad-mda7-treated H1299-Neo tumors. Our findings thus showed that the NF-kappaB activation induced by Ad-mda7 treatment of lung cancer cells is an intrinsic survival mechanism and that the inhibition of this NF-kappaB expression results in enhanced tumor cell killing.
authors: Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Unit 445, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors: Yasuhisa
authors: Y
authors: Oida
authors: Began
authors: B
authors: Gopalan
authors: Ryo
authors: R
authors: Miyahara
authors: Cynthia D
authors: CD
authors: Branch
authors: Paul
authors: P
authors: Chiao
authors: Sunil
authors: S
authors: Chada
authors: Rajagopal
authors: R
authors: Ramesh
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D015316:Genetic Therapy; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007378:Interleukins / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D013997:Time Factors; D000099180:Interleukin-24
chemical_list: D053148:Caspase 3; D020672:I-kappa B Proteins; D007378:Interleukins; D048728:MAP Kinase Kinase Kinase 1; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D000099180:Interleukin-24; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C482576:MAP3K1 protein, human