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Research Articles: Therapeutics, Targets, and Development

Inhibition of nuclear factor-B augments antitumor activity of adenovirus-mediated melanoma differentiation-associated gene-7 against lung cancer cells via mitogen-activated protein kinase kinase kinase 1 activation

Departments of ¹ Thoracic and Cardiovascular Surgery and ² Surgical Oncology, The University of Texas M. D. Anderson Cancer Center; and ³ Introgen Therapeutics, Inc., Houston, Texas

Requests for reprints: Rajagopal Ramesh, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Unit 445, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-9144; Fax: 713-794-4901. E-mail: rramesh{at}mdanderson.org

Abstract

Nuclear factor-B (NF-B) activation promotes cell survival and growth. Reports show that chemotherapeutic agents and cytokines that are used for cancer therapy activate NF-B 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-B 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-B activation in a dose- and time-dependent manner before activation of cell death pathways. To establish that inhibition of Ad-mda7–mediated NF-B activation results in enhanced tumor cell killing, H1299 cells that overexpress the dominant-negative IB (dnIB) were treated with Ad-mda7 in vitro. An enhanced growth arrest and apoptosis was observed in Ad-mda7–treated H1299-dnIB compared with H1299-Neo cells. This Ad-mda7–mediated enhanced killing of H1299-dnIB 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-dnIB cells resulted in reduced Ad-mda7–mediated cell killing. In vivo, the treatment of H1299-dnIB 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-dnIB 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-B activation induced by Ad-mda7 treatment of lung cancer cells is an intrinsic survival mechanism and that the inhibition of this NF-B expression results in enhanced tumor cell killing. [Mol Cancer Ther 2007;6(4):1440–9]

Grant support: National Cancer Institute grants RO1-CA 102716 and PO1 CA 06294 (R. Ramesh) and CA 89778, CA 88421, and CA 097598 (S. Chada); Cancer Center Support grant CA 16672; and a sponsored research agreement with Introgen Therapeutics, Inc.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Y. Oida and B. Gopalan contributed equally to this work.

Received 6/26/06; revised 1/24/07; accepted 2/22/07.